JP3889708B2 - Hepatitis C tripeptide inhibitor - Google Patents

Abstract

The present invention relates to tripeptide compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel tripeptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION Hepatitis C virus (HCV) is the most etiological pathogen of 90% of all cases of non-A, non-B hepatitis (Choo et al., 1989, Kuo et al. , 1989). The incidence of HCV infection has become an increasingly serious public health concern with 2-15% of infected patients worldwide. While primary infection with HCV is often asymptomatic, many HCV infections progress to chronic symptoms that can last for decades. Of the incidence of chronic HCV infection, about 20-50% will eventually progress to chronic liver damage (eg, cirrhosis), and 20-30% of these cases will become liver failure or include liver. It has been. From the current age of HCV infection group, HCV morbidity and mortality are expected to triple.

  A recognized treatment for HCV infection uses interferon (IFN), which acts indirectly on HCV infection by stimulating the host's antiviral response. Although IFN therapy is not effective enough, a sustained antiviral response occurs in less than 30% of treated patients. In addition, IFN treatment induces a series of side effects that change the severity of 90% of patients to greater severity (eg: acute pancreatitis, depression, retinopathy, thyroiditis). The combined treatment with IFN and ribavirin showed a slightly higher maintenance response rate, but did not reduce IFN-induced side effects.

  The general strategy for the development of antiviral agents has been to virally inactivate the encoded enzyme essential for viral replication. In the case of HCV, inhibitors that selectively target the HCV serine protease, NS3 are likely to provide an advantageous therapy to treat HCV infection in patients by inhibiting HCV replication.

  In particular, as a selective HCV NS3 serine protease inhibitor, compounds that are effective in inhibiting HCV replication are described in International Application No. PCT / CA99 / 00736, publication number WO 00/09543 entitled Hepatitis C inhibitor tri-peptide. The tripeptide compound. However, these compounds do not sufficiently inhibit or have sufficient ability to inhibit HCV serine protease and therefore cannot provide optimal treatment of HCV infected patients.

  What is needed is a compound that is effective in treating HCV-infected patients by selectively inhibiting HCV NS3 serine protease, and these compounds are suitable cells to sufficiently inhibit HCV replication in the patient's body. It has transparency.

SUMMARY OF THE INVENTION The present invention provides a compound of formula (I):

[Where
(a) R ₁ is Ri Oh optionally 1-3 times optionally substituted C _1-8 alkyl with halo or C _3-7 cycloalkyl le;

(b) m is 2 ;
(c) n is 1 or 2;
(d) R ₂ is C _1-6 alkyl or C _2-6 alkenyl Le, was or, R ₂ is H;

(e) R ₃ is, H, or optionally which may be C _1-8 alkyl substituted with phenyl, C _3-12 aralkyl key alkenyl, was or is a C _4-10 (alkylcycloalkyl), or , R ₃ together with the carbon atom to which it is attached form a C _3-7 cycloalkyl group substituted with C _2-6 alkenyl;

(f) Y is H, phenyl substituted with nitro, pyridyl substituted with nitro, or C _1-6 alkyl (wherein the alkyl may be optionally substituted with OH ) Is;

(g) B is H, C _1-6 alkyl optionally substituted with OH , R ₄ — (C═O) —, R ₄ O (C═O) —, or R ₄ SO ₂ —. It is in;

(h) R ₄ is
(i) optionally phenyl, carboxyl, 1 -3 halogen, hydroxy, -OC (O) C _1-6 alkyl, C _1-6 alkoxy sheet is a good C _1-10 alkyl optionally substituted with; or -O-phenyl optionally substituted with halogen or C _1-6 alkoxy;
(ii) optionally C _3-7 cycloalkyl luma other be substituted by hydroxy optionally is Ri C _4-10 alkylcycloalkyl der;
(iv) Tokoro by the Nozomu rehearsal androgenic, be phenyl optionally substituted with nitro;
(v) a furan ring;
(vi) Bicyclo (1.1.1) pentane;
(vii) -C (O) OC 1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl]

In compounds represented, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  The present invention is also a pharmaceutical composition effective for inhibiting HCV NS3 protease or for treating a patient infected with hepatitis C virus, comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, The present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a solvate or prodrug and a pharmaceutically acceptable carrier.

  The present invention is further a method for treating a mammal infected with hepatitis C virus, characterized in that the mammal comprises administration of an effective amount of a compound of the present invention or a salt, solvate or prodrug thereof. On how to do.

  Furthermore, the present invention still further relates to a method of inhibiting HCV NS3 protease, comprising administering to a patient an effective amount of a compound of the present invention or a pharmaceutical salt, solvate or prodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following definitions apply unless otherwise indicated. When (R) or (S) is used to define the configuration of a substituent in relation to the whole compound, it does not relate only to the substituent.

  As used herein, the term “halo” refers to a halogen substituent selected from bromine, chlorine, fluorine or iodine.

The term “C _1-6 alkyl” as used herein refers to a non-cyclic, straight chain or branched chain alkyl substituent containing 1 to 6 carbon atoms, for example methyl, ethyl, Including propyl, butyl, tert-butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.

The term “C _2-10 alkenyl” as used herein, alone or in combination with other residues, refers to an alkyl group as defined above containing 2 to 10 carbon atoms, and further includes at least one divalent Includes double bonds. For example, alkenyl includes allyl and ethenyl.

  Haloalkyl refers to an alkyl group substituted with one or more halo groups, such as trifluoromethyl and the like.

As used herein, the term “C _1-6 alkoxy” refers to an —O (C _1-6 alkyl) group, where alkyl is as defined above containing up to 6 carbon atoms. . Alkoxy is, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. The latter group is usually known as tert-butoxy.

The terms “” and “C _1-6 haloalkoxy” as used herein refer to the group —O (C _1-6 haloalkyl), wherein haloalkyl is as defined above.

The term “C _1-6 alkanoyl” as used herein refers to a linear or branched 1-oxo-alkyl group containing 1 to 6 carbon atoms, for example, formyl, acetyl, 1-oxopropyl. (Propionyl), 2-methyl-1-oxopropyl, 1-oxohexyl and the like.

The term “C _3-7 cycloalkyl” as used herein refers to a cycloalkyl substituent containing from 3 to 7 carbon atoms, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. .

などの「スピロ」−環状基を含む。 The term also refers to spiro-cyclopropyl or spiro-cyclobutyl:

Including "spiro" -cyclic groups.

  The term “unsaturated cycloalkyl” as used herein includes, for example, cyclohexenyl.

The term “C _4-10 alkylcycloalkyl” as used herein is a cycloalkyl group containing from 3 to 7 carbon atoms attached to an alkyl group, wherein the attached group is up to 10 carbon atoms. For example, cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, or cycloheptylethyl.

The term “C _3-7 cycloalkoxy” as used herein is a C _3-7 cycloalkyl group attached to an oxygen atom, for example, butyloxy or cyclopropyloxy.

As used herein, the term “C ₆ or C ₁₀ aryl” refers to an aromatic monocyclo group containing 6 carbon atoms or an aromatic bicyclo group containing 10 carbon atoms, eg, aryl is phenyl, 1-naphthyl. Or 2-naphthyl.

The term “C _7-16 aralkyl” as used herein refers to a C ₆ or C ₁₀ aryl attached to an alkyl group and includes, for example, benzyl, butylphenyl and 1-naphthylmethyl.

のアミノアラルキルなどである。 As used herein, the term “aminoaralkyl” refers to an amino group substituted with a C _7-16 aralkyl group, including:

Such as aminoaralkyl.

である。 As used herein, the term “(C _1-6 alkyl) amide” refers to an amide mono-substituted with C _1-6 alkyl, eg,

It is.

The terms used in the specification, "carboxy (C _1-6 alkyl)" refers to binding with carboxyl group (COOH) through C _1-6 alkyl as defined above, including, for example, butyric acid.

のヘテロシクロが含まれる。 The term “heterocyclo” as used herein includes 5-, 6- or 7-membered saturated or unsaturated (including aromatics) containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. ) A monovalent group derived by removing one hydrogen from a heterocycle. Furthermore, the term heterocyclo includes heterocyclo as defined above fused to one or more ring structures. Examples of suitable heterocyclo include, but are not limited to, pyrrolidine, tetrahydrofuran, thiazolidine, thiazolidine, pyrrole, thiophene, diazepine, 1H-imidazole, isoxazole, thiazole, tetrazole, piperidine, 1,4-dioxane, 4-morpholine, pyridine, pyrimidine, thiazole [4,5-b] -pyridine, quinoline, or indole, or:

Of heterocyclo.

を含む。 The term “C _1-6 alkyl-heterocycle” as used herein is attached through a chain or branched alkyl group (wherein alkyl as defined above containing 1 to 6 carbon atoms). Refers to the heterocyclic group defined above. C _1-6 alkyl-Het is:

including.

  As used in naming the compounds of the present invention, the names “P1 ′, P1, P2, P3, and P4” as used herein are the amino acid residues of the protease inhibitor that bind with respect to the binding of the natural peptide cleavage substrate. Indicates the relative position of the group. If the non-prime position designates an amino acid starting from the C-terminus of the peptide natural cleavage site extending towards the N-terminus, the cleavage occurs in the natural substrate between P1 and P1 '; Exits from the site-specified N-terminus and extends toward the C-terminus. For example, P1 'refers to the first position away from the right side of the C-terminus of the cleavage site (ie, the first position of the N-terminus); whereas P1 is numbered from the left side of the C-terminus of the cleavage site. Starting (P2: second position from C-terminal, etc.) (see Berger A. & Schechter I., Transactions of the Royal Society, London series (1970), B257, 249-2463).

に示す。 That is, in the compound represented by the formula (I), the part of “P1 ′ to P4” in the molecule is

Shown in

で示される化合物をいう。 As used herein, the term “1-aminocyclopropyl-carboxylic acid” refers to:

The compound shown by these.

で示される化合物をいう。 The term “tert-butylglycine” as used herein refers to:

The compound shown by these.

  With respect to amino acids or amino acid derivatives, the term “residue” refers to a group derived from the corresponding α-amino acid by removing the hydroxyl of the carboxy group and one hydrogen of the amino acid group. For example, the terms Gln, Ala, Gly, Ile, Arg, Asp, Phe, Ser, Leu, Cys, Asn, Sar and Tyr are L-glutamine, L-alanine, glycine, L-isoleucine, L-arginine, L -Shows "residues" of aspartic acid, L-phenylalanine, L-serine, L-leucine, L-cysteine, L-asparagine, sarcosine and L-tyrosine, respectively.

With respect to amino acids or amino acid residues, the term “side chain” refers to a group attached to the α-carbon atom of an α-amino acid. For example, the R-group side chain is hydrogen for glycine, methyl for alanine, and isopropyl for valine. See AL Lehninger's text on biochemistry for specific R-groups of α-amino acids, ie side chains (see Chapter 4).

For the compounds of the present invention, preferably m is 2. Preferably, n is 1. Further preferably, R ₂ is ethyl or ethenyl. Further preferably, R ₁ is cyclopropyl, cyclobutyl or optionally substituted phenyl.
Further preferably, R ₁ is cyclopentyl.

で示される構造を有し、ここで、Ｒ₃、ＢおよびＹは、式(Ｉ)における定義と同じであるが、Ｒ₁₁は、Ｃ₁₋₈アルキル、Ｃ₃₋₇シクロアルキル、またはＣ₄₋₁₀(アルキルシクロアルキル)、ナフチル、またはフェニル(ここで、上記フェニルは、所望により、ハロ、ハロアルキル、ハロアルキルオキシ、シアノ、ニトロ、Ｃ₁₋₆アルキル、Ｃ₁₋₆アルコキシ、−ＣＯＯＣＨ _３ またはフェニルで１〜３回置換されていてもよい)である。さらに、Ｒ₁₂は、Ｃ₁₋₆アルキル、Ｃ₂₋₆アルケニルまたはＨである。 In a preferred embodiment, the compounds of the invention have the formula (II):

Wherein R ₃ , B and Y are as defined in formula (I), but R ₁₁ is C _1-8 alkyl, C _3-7 cycloalkyl, or C _4-10 (alkyl cycloalkyl), naphthyl, or phenyl (wherein the phenyl is optionally halo, haloalkyl, haloalkyloxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, —COOCH ₃ Or it may be substituted 1-3 times with phenyl). Further, R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl or H.

  The present invention further includes salts, prodrugs, and pharmaceutical compositions comprising a compound of formula (II), and a compound of formula (II), or a salt, solvate, prodrug thereof.

の構造を有し、ここで、Ｒ₃、ＢおよびＹは、式(Ｉ)における定義と同じであり、Ｒ₁₁は、式(II)における定義と同じである。好ましくは式(III)の化合物において、Ｒ₁₁は、シクロプロピル、シクロブチルまたは所望により置換されているフェニルから選ばれる。本発明は、さらに、式(III)の化合物の塩、溶媒和物、プロドラッグ、および式(III)の化合物、またはその塩、溶媒和物、プロドラッグを含む医薬組成物を含む。 Furthermore, in a preferred embodiment, the compounds of the invention have the formula (III):

Where R ₃ , B and Y are the same as defined in formula (I) and R ₁₁ is the same as defined in formula (II). Preferably in the compound of formula (III) R ₁₁ is selected from cyclopropyl, cyclobutyl or optionally substituted phenyl. The present invention further includes salts, solvates, prodrugs of compounds of formula (III), and pharmaceutical compositions comprising compounds of formula (III), or salts, solvates, prodrugs thereof.

の構造を有し、ここで、Ｒ₃、ＢおよびＹは、式(Ｉ)における定義と同じであり、Ｒ₁₁は、式(II)における定義と同じである。好ましくは、式(IV)の化合物において、Ｒ₁₁は、シクロプロピル、シクロブチルまたは所望により置換されているフェニルから選ばれる。本発明は、さらに、式(IV)の化合物の塩、溶媒和物、プロドラッグ、および式(IV)の化合物、またはその塩、溶媒和物、プロドラッグを含む医薬組成物を含む。 In another preferred embodiment, the compound of the invention has formula (IV):

Where R ₃ , B and Y are the same as defined in formula (I) and R ₁₁ is the same as defined in formula (II). Preferably, in the compound of formula (IV), R ₁₁ is selected from cyclopropyl, cyclobutyl or optionally substituted phenyl. The present invention further includes salts, solvates, prodrugs of compounds of formula (IV), and pharmaceutical compositions comprising compounds of formula (IV), or salts, solvates, prodrugs thereof.

の化合物であり、ここで、Ｒ₃、ｎ、ＢおよびＹは、式(Ｉ)における定義と同じであり、Ｒ₁₁は、式(II)における定義と同じであり、ｐは、１−３である。 Another preferred embodiment is represented by formula (V):

Wherein R ₃ , n, B and Y are as defined in formula (I), R ₁₁ is as defined in formula (II), and p is 1-3. It is.

Preferably, in the compound of formula (V), R ₁₁ is selected from cyclopropyl, cyclobutyl or optionally substituted phenyl. The compounds of the present invention include helically correlated diastereomers of the compound of formula (V), where the diastereomers are either a mixture or a single diastereomer, Prepared individually or separated from the diastereomeric mixture.

  The present invention further includes salts, solvates, prodrugs of the compound of formula (V), and pharmaceutical compositions comprising a compound of formula (V), or a salt, solvate, prodrug thereof.

In yet another preferred embodiment, the compound of the present invention has the formula:

[Where
(a) R ₃₁ is C _1-8 alkyl, C _3-7 cycloalkyl, or C _4-10 (alkyl cycloalkyl), all optionally substituted with hydroxy, halo, C _{1 -6} alkoxy, C _1-6 thioalkyl, amide, amino, (C _1-6 alkyl) amide, C ₆ or C ₁₀ aryl, C _7-16 aralkyl, Het, or (C _1-6 alkyl) -Het The aryl, arylalkyl or Het is optionally substituted with halo, alkyl or lower alkyl-Het;
(b) n is 1 or 2;
(c) R ₃₂ is H, C _1-6 alkyl, C _1-3 alkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl, all optionally substituted with halogen May be;

(d) R ₃₃ is C _1-8 alkyl, C _3-12 alkenyl, C ₃ -C ₇ cycloalkyl, C _4-13 cycloalkenyl, or C ₄ -C ₁₀ (alkyl cycloalkyl), optionally everything hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, amino, amido, may be substituted with (lower alkyl) amido, C ₆ or C ₁₀ aryl or C ₇ -C ₁₆ aralkyl;

(e) Y ₂ is H or C ₁ -C ₆ alkyl;
(f) B ₂ is H, R _{14- (} C═O) —; R ₁₄ O (C═O) —, R ₁₄ —N (R ₁₅ ) —C (═O) —; R ₁₄ —N ( R ₁₅ ) —C (═S) —; R ₁₄ SO ₂ —, or R ₁₄ —N (R ₁₅ ) —SO ₂ —;

(g) R ₁₄ is
(i) Amino, amide, or (lower alkyl) optionally mono- or di-substituted with carboxyl, C _1-6 alkanoyl, hydroxy, C _1-6 alkoxy, optionally C _1-6 alkyl C _1-10 alkyl _optionally substituted with amide;
(ii) C _3-7 cycloalkyl, C _3-7 cycloalkoxy, or C _4-10 alkylcyclo-alkyl, all optionally hydroxy, carboxyl, (C _1-6 alkoxy) carbonyl, optionally C _{1 May be} substituted with amino, amide or (lower alkyl) amide, optionally mono- or disubstituted with _-6 alkyl;
(iii) an amino optionally mono- or disubstituted with C _1-6 alkyl; an amide; or a (lower alkyl) amide;
(iv) C ₆ or C ₁₀ aryl or C _7-16 aralkyl, optionally all mono- or di-substituted with C _1-6 alkyl, hydroxy, amide, (lower alkyl) amide or optionally C _1-6 alkyl Optionally substituted with an optionally substituted amino; or
(v) Het or (lower alkyl) -Het, both optionally mono- or disubstituted with C _1-6 alkyl, hydroxy, amide, (lower alkyl) amide, or optionally C _1-6 alkyl Optionally substituted with amino; and
(h) R ₁₅ is H or C _1-6 alkyl]
It is a compound shown by these.

  The present invention further includes salts, solvates, prodrugs of compounds of formula (VI) and pharmaceutical compositions comprising compounds of formula (VI), or salts, solvates, prodrugs thereof.

  The compounds of the present invention can form salts with the basic moiety by the addition of a pharmaceutically acceptable acid. Acid addition salts can be prepared from compounds of formula (I) and include, but are not limited to, pharmaceutically acceptable inorganic acids, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid. Organic acids include p-toluenesulfonic acid, methanesulfonic acid, acetic acid, benzoic acid, citric acid, malonic acid, fumaric acid, maleic acid, succinic acid, succinic acid, sulfamic acid, tartaric acid and the like. Thus, examples of such pharmaceutically acceptable salts include chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, citrate, acetate, malonate, fumaric acid Salt, sulfamate and tartrate.

  Salts of amine groups also include quaternary ammonium salts where the amino nitrogen has a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl group.

  A compound of the present invention that is substituted with a base group may be a salt formed by the addition of a base. Such base addition salts include, for example, salts derived from inorganic bases including alkali metal salts (eg, sodium and potassium), alkaline earth metal salts (eg, calcium and magnesium), aluminum salts and ammonium salts. included. Furthermore, suitable base addition salts are, for example, trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N, N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine, Tri- (2-hydroxyethyl) amine, procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabiethylamine, N, N′-bishydroabiethylamine, glucamine, N-methylglucamine, collidine, quinine, Quinoline, ethylenediamine, ornithine, choline, N, N'-benzylphenethylamine, chloroprocaine, diethanolamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane and tetramethyl hydroxide Moniumu and including lysine, salts of physiologically acceptable organic bases such as basic amino acids such as arginine and N- methyl-glutamine. These salts can be prepared by methods known to those skilled in the art.

  Some of the compounds of the present invention and salts thereof are also solvates with water, such as hydrates, or solvates formed with organic solvents such as methanol, ethanol or acetonitrile, methanolate, ethanol, respectively. It may be a rate or an acetonitrile. The present invention includes each solvate and mixtures thereof.

  The invention also includes pharmaceutically acceptable prodrugs of the compounds of the invention. Prodrugs are derived from compounds of the present invention that have chemically or metabolically cleavable groups and become pharmaceutically active compounds of the present invention under solvation or physiological conditions in vivo. Prodrugs of the compounds of formula (I)-(VI) may be formed in a conventional manner with the functional groups of the compounds and amino, hydroxy or carboxy groups. Prodrug derivative forms often offer advantages such as solubility, histocompatibility, delayed release in mammalian organs (Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, for example, esters prepared by reaction of the parent acid compound with a suitable alcohol, or by reaction of the parent acid compound with a suitable amine. Including amide. If present, simple aliphatic or aromatic esters derived from acid groups hanging on the compounds of the present invention are preferred as prodrugs. In some cases it is desirable to produce double ester forms such as (acyloxy) alkyl esters or (alkoxycarbonyl) oxy) alkyl esters.

  Furthermore, the compounds of the invention, or salts, solvates or prodrugs thereof, may be polymorphic. The present invention also includes such polymorphic forms.

[式中、Ｃ₁およびＣ₂は、各々、シクロプロピル環の１および２位の不斉炭素原子を示す]で示されるＰ1シクロプロピル構成成分を含む。式(Ｉ)−(IV)および(VI)の化合物の他の部分の他の可能性のある不斉炭素中心にもかかわらず、これら２つの不斉炭素中心の存在は、式(Ｉ)−(IV)および(VI)の化合物は、例えば、下記：

に示すような式(Ｉ)−(IV)および(VI)の化合物(ここで、Ｑは、アミドに対してsyn、またはカルボニルに対してsynのいずれかに配置されている)のジアステレオマーなどのジアステレオマーのラセミ混合物として存在し得ることを意味する。 The compounds of the invention (formulas (I)-(IV) and (VI)) also contain two or more chiral centers. For example, the compounds of formulas (I)-(IV) and (VI) have the formula:

Wherein C ₁ and C ₂ represent the asymmetric carbon atoms at the 1 and 2 positions of the cyclopropyl ring, respectively, and contain the P 1 cyclopropyl component. Despite other possible asymmetric carbon centers in other parts of the compounds of formulas (I)-(IV) and (VI), the presence of these two asymmetric carbon centers is Compounds of (IV) and (VI) are for example:

Diastereomers of the compounds of the formulas (I)-(IV) and (VI) as shown in the formula (wherein Q is arranged in either syn for amide or syn for carbonyl) It can exist as a racemic mixture of diastereomers such as

  The present invention includes, for example, both enantiomers and mixtures of enantiomers, for example racemic mixtures.

  As described in the examples below, racemic mixtures can be prepared and then resolved into individual optical isomers, or these optical isomers can also be prepared by chiral synthesis.

  Enantiomers can be resolved by methods known to those skilled in the art, for example dialysis that can be separated by crystallization, gas-liquid or liquid chromatography, selective reaction of an enantiomer specific reagent with one enantiomer. By formation of stereoisomeric salts. It will be appreciated that when the desired enantiomer is converted to another chemical by separation techniques, additional steps are required to produce the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by converting an optically active reagent, substrate, catalyst or solvent, or one enantiomer to the other by asymmetric substitution.

  Certain compounds of the present invention may also exist in different stable steric forms that are separable. With respect to asymmetric single bonds, twisted asymmetric carbons can be separated into individual configurations due to, for example, limited rotation of the ring due to steric hindrance or ring distortion. The present invention includes the individual configurational isomers of these compounds or mixtures thereof.

  Certain compounds of the present invention may also be in zwitterionic form, and the present invention includes zwitterionic forms of these compounds or mixtures thereof.

  The compounds of the present invention are effective in inhibiting HCV NS3 protease and preventing or treating hepatitis C virus infection and subsequent treatment of pathological symptoms. The treatment treats a patient in need of such treatment with a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical carrier and a compound of the invention, or pharmaceutical Administration of a pharmaceutical composition comprising an effective amount of an acceptable salt, solvate or prodrug.

  It will be appreciated by those skilled in the art that references herein to prophylaxis extend to prophylaxis and treatment of distinct infections or symptoms. This includes initiation of treatment before and after virus exposure. Further, the present invention provides immunomodulators such as α-, β-, or γ-interferon; other antiviral agents such as ribaviran, amantadine; other HCV NS3 protease inhibitors; inhibition of other targets during the HCV life cycle An agent that can be administered in conjunction with, but not limited to, helicase, polymerase, metalloprotease, or intra-sequence ribosome entry site (IRES); or combinations thereof. Additional agents can be mixed with the compounds of the present invention to take a single dosage form. Alternatively, these additional agents can be administered separately to the mammal as part of multiple dosage forms.

  These methods are effective in reducing mammalian HCV NS3 protease activity. If the pharmaceutical composition contains only the compound of the present invention as an active ingredient, such a method further adds to the mammal the immunomodulator, antiviral agent, HCV protease inhibitor or helicase, polymerase, metallo Administering an agent selected from inhibitors of other targets in the HCV life cycle, such as proteases or IRES. Such additional agents can be administered before, simultaneously with, or after administration of the composition of the invention to the mammal.

  The compounds of the present invention are also useful for their production and screening and replication testing of antiviral compounds. Furthermore, the compounds of the present invention are useful for demonstrating or determining the binding site of other antiviral compounds to HCV NS3 protease, eg, by competitive inhibition.

  The compounds of the present invention are usually non-toxic, pharmaceutically acceptable by oral, parenteral (including subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion), by inhalation spray or rectally. Can be administered in dosage unit formulations containing carriers, adjuvants and excipients.

  The present invention also provides a pharmaceutical composition for use in the above treatment method. The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier, excipient or diluent in combination with an effective amount of a compound of formula I-VI.

  The active ingredient in such formulations comprises from 0.1 weight percent to 99.9 weight percent of the formulation. “Pharmaceutically acceptable” means that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

  This pharmaceutical composition is manufactured using well-known and easily available components by known operating methods. The composition of the present invention can be formulated so that the active ingredient is released immediately, sustained, or delayed after administration to a patient using methods known to those skilled in the art. In preparing the compositions of the present invention, the active ingredient is usually admixed with the carrier or diluted by the carrier or encapsulated in a carrier that is in the form of a capsule, sachet, drug wrapper or other container. When the carrier acts as a diluent, the carrier may be a solid, semi-solid or liquid that serves as a vehicle for excipients, extenders or active ingredients. That is, the composition comprises tablets, pills, powders, beadlets, troches, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), soft and hard gelatin capsules, suppositories. It may be in the form of a sterile injection, a sterile packaging powder, or the like.

  The compounds can be administered by a variety of routes including oral, intranasal, rectal, transdermal, subcutaneous, intravenous, intramuscular and nasal.

  When administered orally, these compositions are prepared by techniques well known in the pharmaceutical formulation art. For oral administration, the compounds are typically formulated with additives such as binders, fillers, lubricants, extenders, diluents, disintegrants and the like known in the art.

  For parenteral administration, the compounds are non-toxic and parenterally acceptable pharmaceutically, such as mannitol, 1,3-butanediol, water, 5 percent glucose, Ringer's solution, isotonic sodium chloride solution. Formulated with a suitable dispersing or wetting and suspending agent such as an acceptable diluent or solvent, or a fixed oil containing fatty acids including sterile, low toxicity synthetic mono- or di-glycerides and oleic acid.

  The compounds of the invention, salts or solvates thereof may be formulated into unit dosage formulations containing dosages of about 0.1 mg to about 1000 mg, or more, according to the specific treatment. An example of a unit dosage formulation contains 5 mg of a compound of the invention in a 10 mL sterile glass ampoule. Another example of a unit dosage formulation includes about 10 mg of a compound of the present invention as its pharmaceutically acceptable salt in 20 mL of isotonic saline contained in a sterile ampoule.

  The compounds of the invention can also be administered to humans in a dosage range of 1-100 mg / kg body weight in divided doses. A preferred dose is 1-20 mg / kg body weight divided by oral administration. However, the specific dose concentration and frequency for a particular patient depends on the specific compound used, the metabolic stability and duration of action of the compound, the route of administration, age, weight, health, sex, dietary restriction, method of administration Naturally, it can vary depending on and depends on various factors such as time, excretion rate, combination of drugs, severity of specific symptoms and patient being treated.

  The general methods useful for the synthesis of the compounds specifically listed in this invention are shown below. The preparations shown below are disclosed for illustrative purposes only and are not meant to be construed as limiting the method of preparation of compounds by other methods.

  One skilled in the art will appreciate that a number of methods can be used to prepare the compounds of the present invention. These compounds can be made by methods including methods known in the chemical arts for the preparation of structural analogs, or by the novel methods described herein. These compounds (or pharmaceutically acceptable salts thereof) and methods for producing novel intermediates for the production of these compounds are also the main points of the present invention, and are specifically described by the following methods. Here, unless otherwise specified, the meanings of general groups are the same as defined above. For the preparation of such compounds, it is naturally preferred or necessary to protect the functional group with a conventional protecting group and then remove the protecting group to obtain the compound of the invention. .

The compounds of the present invention are represented by Scheme I:
Reaction formula I

(Wherein CPG is a carboxyl protecting group and APG is an amino protecting group).

  In summary, P1, P2 and P3 can be combined by known peptide coupling techniques. The P1, P2 and P3 groups can be linked together in any order as long as the final compound corresponds to a peptide of formula I-VI. For example, P3 can be bound to P2-P1; or P1 can be bound to P3-P2.

  In general, peptides couple the unprotected carboxyl group of the next appropriately protected N-protected amino acid by deprotection of the amino-group of the N-terminal residue and peptide bonds using the described methods. Can be stretched. This deprotection and coupling method is repeated until the desired sequence is obtained. This coupling can be performed stepwise with the constituent amino acids as illustrated in Scheme I. Coupling between two amino acids, amino acids and peptides, or two peptides, or two peptide fragments can be performed by the azide method, mixed carbonyl-carboxylic anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide). , Diisopropylcarbodiimide or water-soluble carbodiimide) method, active ester (p-nitrophenyl ester, N-hydroxysuccinimide ester) method, Woodward reagent K-method, carbonyldiimidazole method, phosphorus reagent or oxidation-reduction method, etc. This can be done using standard coupling methods. Some of these methods (especially the carbodiimide method) are facilitated by the addition of 1-hydroxybenzotriazole or 4-DMAP. These coupling reactions can be performed either in solution (liquid phase) or solid phase.

More specifically, the coupling step involves dehydrative coupling of the free carboxyl of one reactant with the free amino group of the other reactant in the presence of a coupling agent to produce a linked amide bond. . Such coupling agents peptide chemistry general textbooks, for example, M. Bodanszky, "Peptide Chemistry ", 2 nd rev ed., Springer-Verlag, Berlin, Germany, have been described in (1993). Examples of suitable coupling agents are 1, hydroxybenzotriazole in the presence of N, N'-dicyclohexylcarbodiimide or N-ethyl-N '-[(3-dimethylamino) propyl] carbodiimide. Practical and useful coupling agents are commercially available, as is or in the presence of 1-hydroxybenzotriazole or 4-DMAP (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluoro It is phosphate. Another practical and useful coupling agent is commercially available, 2- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate. . Also, practical and useful coupling agents are commercially available, O- (7-azabenzotrizol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluoro. It is phosphate.

  The coupling reaction is performed in an inert solvent such as dichloromethane, acetonitrile or dimethylformamide. An excess of tertiary amine such as diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine or 4-DMAP is added to the reaction mixture to maintain a pH of about 8. The reaction temperature is usually 0 ° C. to 50 ° C., and the reaction temperature is usually 15 min to 24 h.

  The functional groups of the constituent amino acids generally must be protected to avoid the formation of undesired bonds during the coupling reaction. Green, “Protective Groups in Organic Chemistry”, John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology”, Vol. 3, Academic Press, New York (1981) Which is incorporated herein by reference.

  The α-amino group of each amino acid to be coupled to the growing peptide must be protected (APG). Any protecting group known in the art can be used. Examples of such groups include 1) acyl groups such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl; 2) benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyl and 9-fluorene. Aromatic carbamate groups such as nylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamates such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and aryloxycarbonyl; 4) cyclopentyloxycarbonyl and adamantyloxycarbonyl 5) alkyl groups such as triphenylmethyl and benzyl; 6) trialkylsilyl such as trimethylsilyl; and 7) thiol-containing groups such as phenylthiocarbonyl and dithiasuccinoyl. It is.

  Preferred α-amino protecting groups are either Boc or Fmoc. Many amino acid derivatives that are appropriately protected for peptide synthesis are commercially available.

  The α-amino protecting group of the newly added amino acid residue is cleaved before coupling of the next amino acid. When Boc is used, the select method uses trifluoroacetic acid as is or in dichloromethane, or HCl in dioxane or ethyl acetate. The resulting ammonium salt is then neutralized either before coupling or in situ with an aqueous buffer or a basic solution such as a tertiary amine in dichloromethane or acetonitrile or dimethylformamide. When the Fmoc group is used, the selected reagent is piperidine or substituted piperidine in dimethylformamide, but secondary amines can also be used. Deprotection is performed at a temperature of 0 ° C. to room temperature (rt or RT), usually 20-22 ° C.

  Amino acids with side chain functional groups must be protected during the production of the peptide using any of the groups described above. One skilled in the art will appreciate that the selection and use of suitable protecting groups for these side chain functional groups depend on the presence of amino acids and other protecting groups in the peptide. The choice of such protecting group is important because the group must not be removed during the deprotection and coupling of the α-amino group.

  For example, when Boc is used as the α-amino protecting group, the following side chain protecting groups are suitable: p-Toluenesulfonyl (tosyl) is used to protect the amino side chain of amino acids such as Lys and Arg. An acetamidomethyl, benzyl (Bn), or tert-butylsulfonyl group can be used to protect the sulfide-containing side chain of cysteine; benzyl (Bn) ether is a hydroxy-containing side chain of serine, threonine or hydroxyproline And benzyl esters can be used to protect the carboxy-containing side chains of aspartic acid and glutamic acid.

  When Fmoc is chosen for α-amine protection, usually tert-butyl based protecting groups are safe. For example, Boc is used for lysine and arginine, tert-butyl ether is used for serine, threonine and hydroxyproline, and tert-butyl ester is used for aspartic acid and glutamic acid. The triphenylmethyl (trityl) group can be used to protect the sulfide-containing side chain of cysteine.

  When the peptide extension is complete, all protecting groups are removed. When using liquid phase synthesis, the protecting group is removed in any manner dictated by the choice of protecting group. These methods are well known to those skilled in the art.

Furthermore, the following guidance is provided in the preparation of the compounds of the present invention. For example, to synthesize compounds that are R ₄ —C (O) —, R ₄ —S (O) ₂ , protected P 3 or the entire peptide or peptide moiety is attached to the appropriate acyl chloride or sulfonyl chloride, respectively. However, it is either commercially available or its synthesis is well known to those skilled in the art.

In the preparation of compounds that are R ₄ O—C (O) —, the protected P 3 or the entire peptide or peptide portion is coupled to the appropriate chloroformate, which is either commercially available or synthesized. Well-known to vendors. For Boc-derivatives, (Boc) ₂ O is used.

a)シクロペンタノールをホスゲンで処理し、対応するクロロホーメートを得る。
b)クロロホーメートを、トリエチルアミンなどの塩基の存在下、所望のＮＨ₂−トリペプチドで処理し、シクロペンチルカルバメートを得る。 For example:

a) Treat cyclopentanol with phosgene to obtain the corresponding chloroformate.
The b) chloroformate in the presence of a base such as triethylamine, the desired NH ₂ - is treated with the tripeptide to give the cyclopentyl carbamate.

In the preparation of a compound of R ₄ —N (R ₅ ) —C (O) —, or R ₄ —NH—C (S) —, the protected P 3 or the entire peptide or part of the peptide is converted with phosgene and then with SynLett Feb 1995; (2); Treat with amine as described in 142-144 or react with a suitable base such as commercially available isocyanate and triethylamine.

In the preparation of the compound R ₄ —N (R ₅ ) —S (O ₂ ), the protected P 3 or the whole peptide or peptide part is either freshly prepared or commercially available sulfamyl chloride, then patent Ger. Offen. (1998), 84 pp. DE 19802350 or treated with an amine as described in WO 98/32748.

  The α-carboxyl of the C-terminal residue is usually protected as an ester (CPG) that is cleaved to a carboxylic acid. The protecting groups used are: 1) alkyl esters such as methyl, trimethylsilylethyl and t-butyl 2) aralkyl esters such as benzyl and substituted benzyl, or 3) mild base treatment or mild reduction such as trichloroethyl and phenacyl esters An ester that is cleaved by means.

The resulting α-carboxylic acid (obtained from mild acid, mild base treatment or mild reduction procedure) is quantitatively determined by treatment of R ₀ SO ₂ NH ₂ [R ₀ SO ₂ Cl in ammonia saturated tetrahydrofuran solution. In the presence of a base such as 4-dimethylaminopyridine (4-DMAP) and / or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), etc. In the presence of the peptide coupling agent, the P1 ′ moiety is incorporated to effectively assemble the tripeptide, P1′-P1-P2-P3-APG.

Furthermore, if the P3 protecting group APG is removed and replaced with part B by the above method, the α-carboxylic acid obtained by cleavage (obtained from mild acid, mild base treatment or mild reduction procedure) R ₀ SO ₂ NH ₂ [prepared quantitatively by treatment of R ₀ SO ₂ Cl in ammonia saturated tetrahydrofuran solution] and 4-dimethylaminopyridine (4-DMAP) and / or 1,8-diazabicyclo [5. 4.0] In the presence of a base such as undec-7-ene (DBU), in the presence of a peptide coupling agent such as CDI or EDAC, the P1 ′ portion is incorporated, and the tripeptide, P1′-P1-P2 -P3-B was prepared.

  The compounds of the present invention are described in the methods described in the Examples below and in US Preliminary Application No. 60 / 249,968, entitled “Hepatitis C Tripeptide Inhibitor”, Campbell and Good, filed Nov. 20, 2000. Can be produced by a number of methods, including The description of US Preliminary Application No. 60 / 249,968 is incorporated herein by reference.

Illustrative Examples The following specific examples illustrate the synthesis of compounds of the present invention and should not be construed as limiting the scope or scope of the invention. The method can be applied to variations and can produce compounds not specifically disclosed but encompassed by the present invention. Furthermore, variations on producing the same compound in somewhat different ways will also be apparent to those skilled in the art.

Unless otherwise indicated, the percentage of solution is expressed in terms of weight to volume and the percentage of solution is expressed in volume to volume. Nuclear magnetic resonance (NMR) spectra are measured on either a Bruker 300, 400 or 500 MHz spectrometer and the chemical shift (δ) is stated in parts per million. Flash chromatography was performed on silica gel (SiO ₂ ) according to Still's flash chromatography technique (WC Still et al., J. Org. Chem., (1978), 43, 2923).

  All liquid chromatography (LC) data were obtained with Shimadzu LC-10AS liquid chromatography using an SPD-10AV UV-Vis detector. Mass spectrometer (MS) data were measured on a Micromass Platform for electrospray (ES +) LC.

Unless otherwise noted, each compound was analyzed by LC / MS using one of seven methods under the following conditions.

Column: (Method A) -YMC ODS S7 C18 3.0x50 mm
(Method B) -YMC ODS-A S7 C18 3.0x50 mm
(Method C) -YMC S7 C18 3.0x50 mm
(Method D) -YMC Xterra ODS S7 3.0 x 50 mm
(Method E) -YMC Xterra ODS S7 3.0x50 mm
(Method F) -YMC ODS-A S7 C18 3.0x50 mm
(Method G) -YMC C18 S5 4.6x50 mm]
Gradient: Solvent A 100% / Solvent B 0% to Solvent A 0% / Solvent B 100%
Gradient time: 2 min. (A, B, D, F, G); 8 min. (C, E)
Maintenance time: 1 min. (A, B, D, F, G); 2 min. (C, E)
Flow rate: 5 mL / min
Detection wavelength: 220 nm
Solvent A: 10% MeOH / 90% H ₂ O / 0.1% TFA
Solvent B: 10% H ₂ O / 90% MeOH / 0.1% TFA

  The compounds and chemical intermediates of the present invention described in the following examples were prepared according to the following methods.

Example 1
Boc- (4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline (below) was prepared as described in Step 1a-c.

Step 1a: Preparation of 4-hydroxy-2-phenyl-7-methoxyquinoline (below)

A solution of m-anisidine (300 g, 2.44 mole) and ethyl benzoyl acetate (234.2 g, 1.22 mole) in toluene (2.0 L) was added to HCL (4.0 N in dioxane, 12.2 mL, 48.8 mmole). The resulting solution was refluxed for 6.5 hr using a Dean-Stark apparatus (approximately 56 ml of aqueous solution was recovered). The mixture was cooled to rt, aqueous HCl (10%, 3x500mL), aqueous NaOH (1.0 N ,. 2x200mL), water (3 × 200 mL) several times partitioned and the organic layer was dried (MgSO _4), in a vacuum Concentration gave an oily residue (329.5 g). The crude product was heated in an oil bath (280 ° C.) for 80 min using a Dean-Stark apparatus (approximately 85 mL of liquid was recovered). The reaction mixture was cooled to rt, the solid residue was triturated with CH ₂ Cl ₂ (400 mL), the resulting suspension was filtered and the filtered solid was further washed with CH ₂ Cl ₂ ( ₂ × 150 mL). did. The resulting solid was dried in vacuo (50 ° C .; 1 torr; 1 day) to give analytically pure 4-hydroxy-7-methoxy-2-phenylquinoline as a light brown solid (60.7 g, 20% total yield). ¹ H NMR δ (DMSO): 3.86 (s, 3H), 6.26 (s, 1H), 6.94 (dd, J = 9.0, 2.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.55− 7.62 (m, 3H), 7.80-7.84 (m, 2H), 8.00 (d, J = 9.0 Hz, 1H), 11.54 (s, lH); ¹³ C NMR (DMSO-d ₆ ) δ: 55.38, 99.69, 107.07, 113.18, 119.22, 126.52, 127.17, 128.97, 130.34, 134.17, 142.27, 149.53, 161.92, 176.48. LC-MS (retention time: 1.26, method D), MS m / z 252 (M ⁺ +1).

Step 1b: Preparation of 4-chloro-7-methoxy-2-phenylquinoline (below)

The product of step 1a (21.7 g, 86.4 mmole) was suspended in POCl ₃ (240 mL). The suspension was refluxed for 2 hours. After removal of POCl ₃ in vacuo, the residue was partitioned between EtOAc (1 L) and cold aqueous NaOH (produced from 1.ON 200 mL NaOH and 20 mL 10.0 N NaOH) and stirred for 15 min. The organic layer was washed with water (2 × 200 mL), brine (200 mL), dried (MgSO ₄ ), concentrated in vacuo and 4-chloro-2-phenyl-7-methoxyquinoline (21.0 g, 90% ) Was obtained as a light brown solid. ¹ H NMR (DMSO-d ₆ ) δ: 3.97 (s, 3H), 7.36 (dd, J = 9.2, 2.6 Hz, 1H), 7.49-7.59 (m, 4H), 8.08 (d, J = 9.2 Hz, 1H), 8.19 (s, 1H), 8.26-8.30 (m, 2H); ¹³ C NMR (DMSO-d ₆ ) δ: 55.72, 108.00, 116.51, 119.52, 120.48, 124.74, 127.26, 128.81, 130.00, 137.58, 141.98, 150.20, 156.65, 161.30. LC-MS (retention time: 1.547, method D), MS m / z 270 (M ⁺⁺ 1).

Step lc: Production of Boc- (4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) -S-proline (below)

To a suspension of Boc-4R-hydroxyproline (16.44 g, 71. 1 mmol) in DMSO (250 mL) was added t-BuOK (19.93 g, 177.6 mmol) at 0 ° C. The resulting mixture was stirred for 1.5 hours, then the product of step 1b (21.02 g, 77.9 mmol) was added in 3 portions over 1 h. The reaction was stirred for 1 day. The reaction mixture was poured into cold water (1.5 L) and washed with Et ₂ O (4 × 200 mL). The aqueous solution was acidified to pH 4.6 and filtered to give a white solid which was dried in vacuo to give the product Boc- (4R)-(2-phenyl-7-methoxyquinoline-4-oxo) proline (32.5 g , 98%). ¹ H NMR (DMSO) δ 1.32, 1.35 (2 s (rotamers) 9H), 2.30−2.42 (m, 1H), 2.62−2.73 (m, 1H), 3.76 (m, 2H), 3.91 ( s, 3H), 4.33−4.40 (m, 1H), 5.55 (m, 1H), 7.15 (dd, J = 9.2, 2.6 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.42 −7.56 (m, 4H), 7.94−7.99 (m, 1H), 8.25, 8.28 (2s, 2H), 12.53 (brs, 1H); LC-MS (retention time: 1.40, method D), MS m / z 465 (M ⁺ +1).

Example 2
1-{[1- (2-tert-butoxycarbonylamino-3-methylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidin-2-carbonyl] amino} -2-ethylcyclopropane -Carboxylic acid (below) was prepared as described in step 2a-2h below.

Step 2a: Preparation of 2-ethylcyclopropane-1,1-dicarboxylic acid di-tert-butyl ester (below)

50% aqueous NaOH solution (92.4 g, 185 mL of H ₂ 0) Medium benzyltriethylammonium chloride (21.0 g, 92.2 mmol) to a suspension of 1,2-dibromobutane (30.0 g, 138.9 mmol) and di - tert-Butyl malonate (20.0 g, 92.5 mmol) was added. The reaction mixture was stirred vigorously at 18 h, rt and a mixture of ice and water was added. Extracted with the crude product CH ₂ Cl ₂ (3x) and then washed with water (3x). Saline and organic extracts were combined. The organic layer was dried (MgSO _4), filtered, and concentrated in vacuo. The resulting residue was subjected to flash chromatography (100 g SiO ₂ , 3% Et ₂ O in hexane) to give the title compound (18.3 g, 67.8 mmol, 73% yield), which was used directly in the next reaction.

Step 2b: Preparation of racemic 2-ethylcyclopropane-1,1-dicarboxylic acid tert-butyl ester (below)

The product of step 2a (18.3 g, 67.8 mmol) was added to a suspension of potassium tert-butoxide (33.55 g, 299.0 mmol) in dry ether (500 mL) at 0 ° C., then H ₂ 0 ( 1.35 mL, 75.0 mmol) was added and stirred vigorously overnight at rt. The reaction mixture was poured into a mixture of ice and water and washed with ether (3x). The aqueous layer was acidified with 10% aq. Citric acid aqueous solution at 0 ° C. and extracted with EtOAc (3 ×). The combined organic layers were washed with water (2 ×), brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a pale yellow oil (10 g, 46.8 mmol, 69% yield). rate).

Step 2c: (1R, 2R) / (1S, 2S) Preparation of 2-ethyl-1- (2-trimethylsilanylethoxycarbonylamino) cyclopropanecarboxylic acid tert-butyl ester (below)

To a suspension of 3 g of freshly activated 4A molecular sieves in the product of step 2b (10 g, 46.8 mmol) and dry benzene (160 mL) was added Et ₃ N (7.50 mL, 53.8 mmol) and DPPA ( 11 mL, 10.21 mmol) was added. The reaction mixture was refluxed for 3.5 h, then 2-trimethylsilylethanol (13.5 mL, 94.2 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered, diluted with Et ₂ O, washed with 10% aqueous citric acid solution, water, saturated aqueous NaHCO ₃ , water (2 ×), brine (2 ×), dried (MgSO ₄ ), and vacuum Concentrated with. The residue was suspended in 120 mL of CH ₂ Cl _{2 with} polyisocyanate impurity removal resin (Aldrich), stirred at rt overnight, and filtered to give the title compound as a pale yellow oil (8 g, 24.3 mmol; 52 %): ¹ H NMR (CDC1 ₃ ) δ 0.03 (s, 9H), 0.97 (m, 5H), 1.20 (bm, 1H), 1.45 (s, 9H), 1.40−1.70 (m, 4H), 4.16 ( m, 2H), 5.30 (bs, 1H).

カルボキシに対してエチルがsyn Step 2d: Preparation of (1R, 2R) / (1S, 2S) 1-amino-2-ethylcyclopropanecarboxylic acid tert-butyl ester (below)

Ethyl to carboxy syn

To the product of step 2c (3 g, 9 mmol) was added 1.0 M TBAF solution in THF (9.3 mL, 9.3 mmol), the mixture was refluxed and heated for 1.5 h, cooled to rt, then diluted with 500 ml of EtOAc. . Solution of water (2 × 100 mL), successively with brine (2 × 100 mL) washed, dried (MgSO _4), and concentrated in vacuo.

Step 2e: 2-ethyl-1-{[4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carbonyl] amino} cyclopropanecarboxylic acid methyl ester (1R, 2R) and (1S , 2S) Production of P1 isomers (below)

A solution of the crude product of step 2d (estimated 9 mmol) in 10 mL of CH ₂ Cl _{2 was} added Boc (4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline 3.5% from step 1c. Added dropwise to a mixture of g (7.53 mmol, 0.84 equiv), HATU 4.1 g (10.8 mmol, 1.2 equiv) and 3 mL NMM in 32 mL CH ₂ Cl ₂ . The solution was stirred at rt for 1 day, diluted with 100 mL of CH ₂ Cl ₂ and then washed with pH 4.0 buffer (4 × 50 mL). The organic layer was washed with saturated aqueous NaHC0 ₃ (100 mL), the aqueous washing was extracted with ethyl acetate (150 mL), the organic layer again pH 4.0 buffer (50 mL), saturated aqueous NaHCO ₃ (50 mL) Washed with. The combined organic solution was dried (MgSO ₄ ), concentrated, and purified twice on an Isco 110 g column (eluting with 20% to 50% EtOAc / hexanes) to give 1.38 g of the (1R, 2R) P1 isomer. 32%) and 1.60 g (37%) of the (1S, 2S) Pl isomer.

(1R, 2R) Pl isomer data: ¹ H NMR (methanol-d ₄ ) δ 0.95-1.05 (m, 3H), 1.11 (dd, J = 9, 5Hz, 1H), 1.38, 1.42, 1.44 (3s , 18H), 1.35−1.69 (m, 4H), 2.35−2.52 (m, 1H), 2.64−2.80 (m, 1H), 3.87−3.97 (m, 2H), 3.95 (s, 3H), 4.37−4.45 (m, 1H), 5.47 (m, 1H), 7.15 (dd, J = 9, 2.4 Hz, 1H), 7.24 (s, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.48-7.55 ( m, 3H), 8.01-8.04 (m, 3H).

(lS, 2S) Pl isomer data: ¹ H NMR (methanol d ₄ ) δ 0.98 (t, J = 7.2 Hz, 3H), 1.12−1.26 (m, 1H), 1.39, 1.41 (two s ( Rotamer) 9H), 1.44 (s, 9H), 1.39--1.69 (m, 4H), 2.35-2.52 (m, 1H), 2.67-2.80 (m, 1H), 3.93 (m, 2H), 3.96 ( s, 3H), 4.36−4.46 (m, 1H), 5.48 (m, 1H), 7.14−7.17 (m, 1H), 7.26 (s, 1H), 7.41 (m, 1H), 7.47−7.57 (m, 3H), 8.02−8.05 (m, 3 H).

Step 2f: (1R, 2R) of 2-ethyl-1-{[4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine-2-carbonyl] -amino} -cyclopropanecarboxylic acid methyl ester Production of Pl isomers (below)

2- (1-tert-Butoxycarbonyl-2-ethylcyclopropyl-1-carbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine-1-carboxylic acid tert- from step 2e The (1R, 2R) P1 isomer of butyl ester (830 mg, 1.3 mmol) was treated with 4N HCl / dioxane 100 mL for 1 day and concentrated in vacuo. The resulting solid was triturated in 100 mL ether to give 2-ethyl-1-{[4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-2-carbonyl] -amino} cyclopropane. - give the carboxylic acid 670 mg (95%), which was directly dissolved in _{60% MeOH / CH 2 Cl 2} 100 mL. The reaction mixture was cooled to 0 ° C., 2 M TMSCHN ₂ 3.1 mL was added and warmed to rt over 10 min. The reaction was completed by 50% and terminated by the dropwise addition of 4N HCl / dioxane, then again returned to the reaction conditions where the reaction was complete, and then terminated with excess 4N HCl / dioxane. The solution was concentrated and 2-ethyl-1-{[4- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2-carbonyl] amino} -cyclopropane-carboxylic acid methyl ester dihydrochloride 700 mg was obtained. ¹ H NMR (methanol d ₄ ) (methanol-d4) δ 0.99 (t, J = 7.2 Hz, 3H), 1.24−1.29 (m, 1H), 1.50−1.68 (m, 4H), 2.55−2.65 (m , 1H), 2.96 (dd, J = 14.7, 7.5 Hz, 1H), 3.71 (s, 3H), 3.96 (bs, 2H), 4.07 (s, 3H), 4.66 (dd, J = 10.3, 7.5 Hz, 1H), 5.97 (s, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.62 (s, 1H), 7.70−7.75 (m, 3H), 8.07−8.09 (m, 2H), 8.42 (d, J = 9.1 Hz, 1H).

If desired, this dihydrochloride salt is converted to the N-BOC analog by reaction with Et ₃ N / (Boc) ₂ O in MeOH to give 2- (1-tert-butoxycarbonyl-2-ethylcyclopropyl- The 1R, 2R P1 isomer of 1-carbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-1-carboxylic acid methyl ester was generated. ¹ H NMR (CDC1 ₃ ) δ 0.99 (t, J = 7 Hz, 3H), 1.15-1.29 (m, 1H), 1.40, 1.44 (2 s (rotamers) 9H), 1.40-1.62 (m , 4H), 2.39−2.46 (m, 1H), 2.65−2.76 (m, 1H), 3.68 (s, 3H), 3.89−3.98 (m, 2H), 3.96 (s, 3H), 4.40−4.45 (m , 1H), 5.48 (m, 1H), 7.16 (dd, J = 9, 2 Hz, 1H), 7.26 (s, 1H), 7.41 (d, J = 2 Hz, 1H), 7.48-7.56 (m, 3H), 8.02-8.05 (m, 3H).

Step 2g: 1-{[1- (2-tert-butoxycarbonyl-amino-3-methyl-butyryl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] Preparation of (1R, 2R) P1 isomers of amino} -2-ethylcyclopropanecarboxylic acid methyl ester (below)

To a suspension of the product of step 2f (120 mg, 0.21 mmol), N-BOC-1-valine (51 mg, 0.23 mmol), NMM (0.10 ml, 0.84 mmol) in DMF (2.5 mL), HATU ( 89 mg, 0.23 mmol) was added at 0 ° C. After stirring for 2 days, the reaction mixture was diluted with EtOAc (80 mL), washed with pH 4.0 buffer (2 × 30 mL), saturated aqueous NaHCO ₃ (30 mL), brine (30 mL) and dried (MgSO ₄ ). And purified on an Isco 10 g column (eluting with 15% to 60% EtOAc in hexanes) to give the title compound as an opaque glass (132 mg, 0.19 mmol, 910). ¹ H NMR δ 0.97-1.01 (m, 6H), 1.13 (m, 1H), 1.23 (dd, J = 9,5 Hz, 1H), 1.27 (s, 9H), 1.44 (dd, J = 8,5 Hz, 1H), 1.52-1.66 (m, 3H), 1.98−2.05 (m, 1H), 2.41−2.47 (m, 1H), 2.71−2.76 (m, 1H), 3.69 (s, 3H), 3.98 ( s, 3H), 4.05−4.12 (m, 2H), 4.59−4.69 (m, 2H), 5.58 (m, 1H), 7.12 (dd, J = 9.2, 2 Hz, 1H), 7.28 (s, 1H) , 7.42 (d, J = 2 Hz, 1H), 8.07, 8.08 (2s, 2H), 8.12 (d, J = 9.2 Hz, 1H). LC-MS (retention time: 1.54, method D), MS m / z 689 (M ⁺ +1).

Step 2h: 1-{[1- (2-tert-butoxycarbonylamino-3-methylbutyryl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine-2-carbonyl] amino} -2 -Preparation of (1R, 2R) P1 isomers of ethylcyclopropanecarboxylic acid (below)

_{THF (7.9 mL), CH 3} 0H (0.8 mL) and H ₂ 0 (4.2 mL) of Step 2g product (124 mg, 0.18 mmol) to a suspension of, LiOH (62 mg, 1.1 mmol ) added did. The reaction mixture was stirred for 2 days, acidified to pH neutral and concentrated in vacuo until only the aqueous layer remained. The resulting aqueous residue was acidified to pH 3.0 by addition of 1.0 N aqueous HCl and extracted with EtOAc (4 × 80 mL). The combined organic solvents were washed with brine (20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound as an opaque glass (100 mg, 0.148 mmol, 82%). ¹ H NMR δ 0.88-1.03 (m, 9H), 1.11 (m, 1H), 1.23 (s, 9H), 1.19-1.70 (m, 5H), 1.96−2.01 (m, 1H), 2.43−2.52 (m , 1H), 2.70−2.77 (m, 1H), 3.98 (s, 3H), 4.00−4.10 (m, 2H), 4.57−4.65 (m, 2H), 5.59 (s, 1H), 7.11−7.15 (m , 1H), 7.30 (s, 1H), 7.41 (m, 1H), 7.53−7.60 (m, 3H), 8.04−8.07 (m, 2H), 8.12 (d, J = 9 Hz, 1H); LC− MS (retention time: 1.50, method D), MS m / z 675 (M ⁺ +1).

Example 3
Compound 1, {1- [2- (2-Ethyl-1-methanesulfonylaminocarbonylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidin-1-carbonyl] -2- The (1R, 2R) Pl isomer of methylpropyl} carbamic acid propyl ester (below) was prepared as follows.

CH ₂ C1 ₂ (1 mL) Medium EDAC (21 mg, 0.11 mmol) in a solution _{of, CH 2 Cl 2 (2 x} 0.5 mL) the product of Step 2h (40 mg, 0.06 mmol) by dividing a solution of 4-DMAP (14.5 mg, 0.11 mmol) and commercially available methanesulfonamide (Aldrich) (11.3 mg, 0.11 mmol) were added. The resulting solution was stirred for 8 days and then DBU (16.7 mg, 0.11 mmol) was added. The reaction was stirred for an additional 2 days, diluted with EtOAc (80 mL), washed with pH 4.0 buffer ( ₃ × 30 mL), aqueous NaHC03 (2 × 30 mL), brine (30 mL), dried (MgSO ₄ ), Isco. Purification on a 10 g column (eluted with 15% to 100% EtOAc in hexane) gave opaque glassy Compound 1 (23.4 mg, 50%). ¹ H NMR (methanol-d ₄ ) 8 0.93-0.97 (m, 9H), 1.13-1.17 (m, 1H), 1.22 (s, 9H), 1.43-1-1.65 (m, 4H), 2.06-2.15 (m, 1H), 2.31−2.40 (m, 1H), 2.62 (dd, J = 14, 7 Hz, 1H), 3.20 (s, 3H), 3.94 (s, 3H), 4.02−4.11 (m, 2H), 4.52 −4.64 (m, 2H), 5.56 (m, 1H), 7.09 (d, J = 9,2 Hz, 1H), 7.23 (s, 1H), 7.38 (d, J = 2 Hz, 1H), 7.47− 7.57 (m 3H), 8.03-8.09 (m, 3H); LC-MS (retention time: 1.45, method D), MS m / z 752 (M ⁺ + l)

  The coupling method described in Example 3 of this specification was performed using an N-acyl sulfone of a tripeptide acid containing either vinyl Acca contained in the product of Step 11e or ethyl Acca contained in the product of Step 2h. It can be used for the production of amide derivatives.

Example 4
Compound 2: {1- [2- (1-cyclo-propanesulfonylamino-carbonyl-2-ethylcyclopropyl carbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine-1-carbonyl The (1R, 2R) Pl isomer of] -2,2-dimethylpropyl} carbamic acid tert-butyl ester (below) was prepared as described in Steps 4a-d.

Step 4a: (1R of (2- (l-Carboxy-2-ethyl-cyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester) , 2R) Production of Pl isomers (below)

To a suspension of 1.55 g (2.83 mmol) of the dihydrochloride of the product of step 2f in 60 mL of CH ₃ CN, 1.60 mL (12 mmol) of TMSCN was added and the mixture was heated to reflux under Ar. Atmosphere for 30 min. . (Boc) ₂ O 0.93 g (4.26 mmol) was added to the resulting solution and the mixture was heated to reflux for 5 h, then cooled to rt. About 10 mL of MeOH was added and the reaction was stirred for 10 min and then concentrated in vacuo. The residue was chromatographed on a Biotage 25M column (eluting with 0-5% MeOH / CH ₂ Cl ₂ ) to give 1.550 g (95%) of the foamy title compound. ¹ H NMR (CD ₃ 0D) δ 1.03 (m, 3H), 1.11-1.56 (m, 3H), 1.44 (s, 9H), 1.66 (m, 2H), 2.47 (m, 1H), 2.65-2.78 ( m, 1 H), 3.95 (s, 5H), 4.41-4.46 (m, 1H), 5.50 (m, 1H), 7.21 (dd, J = 9.0, 2.0 Hz, 1H), 7.31 (s, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.56-7.58 (m, 3H), 7.98-8.08 (m, 3H); ¹³ C NMR (CD ₃ 0D, rotamer, 2 C = O weak to δ 175 (Strength) δ 13.85, 21.69, 23.08, 28.66, 33.90, 37.88, 49.64, 49.93, 53.35, 56.39, 60.53, 78.28, 82.24, 100.82, 105.23, 116.26, 120.29, 124.63, 129.30, 130.20, 131.79, 138.45, 156.26 , 160.16, 164.16, 164.36; LC-MS (retention time: 1.54, method D), MS m / z 575 (M ⁺ +1). HRMS m / z (M + H) ⁺ : C ₃₂ H ₃₈ N ₃ 0 ₇ : Calculated value 576.2710, Actual value 576.2716.

Step 4b: 2- (1-Cyclopropanesulfonylamino-carbonyl-2-ethylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester Of (1R, 1S) isomers (below)

A solution of the product of step 4a (1.55 g, 2.70 mmol) and CDI (0.568 g, 3.50 mmol) in THF (22 mL), DMF (3 mL) and CH ₂ Cl ₂ (25 mL) was refluxed for 60 min. , 2 drops of Et ₃ N were added and the mixture was refluxed for another 30 min, then allowed to cool to room temperature. Cyclopropylsulfonamide (0.424 g, 3.50 mmol) was added in one portion and a solution of DBU (523 O1, 0.291 mmol) was added. The reaction was stirred for 14 h, 150 μl (1 mmol) DBU and 100 mg (0.83 mmol) cyclopropylsulfonamide were added and the mixture was stirred for an additional 11 hours. The mixture was diluted with EtOAc (lOOmL), washed with pH 4.0 buffer (3 × 30 mL), water (20 mL), brine (20 mL), dried (MgSO ₄ ), Biotage 65 M column (CH ₂ C1 ₂ (Eluted with 0% to 5% MeOH) to give the title compound as a foam (1.52, 83%). ¹ H NMR (methanol-d ₄ ) δ 0.94-1.65 (m, 12H), 1.44 (s, 9H), 2.27-2.36 (m, 1H), 2.53-2.59 (m, 1H), 2.933.01 (m, 1 H), 3.93 (s, 3H), 3.87−3.97 (m, 2H), 4.22-4.36 (m, 1H), 5.47 (m, 1H), 7.14 (dd, J = 9.0, 2.0 Hz, 1H), 7.20 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.48-7.56 (m, 3H), 7.97-8.04 (m, 3H); ¹³ C NMR (CD ₃ 0D, rotamer) δ 6.00, 6.30, 6.73, 13.95, 20.83, 23.90, 28.75, 31.72, 32.07, 33.09, 35.41, 36.47, 37.00, 40.56, 56.11, 60.42, 78.07, 82.68, 100.16, 107.54, 116.46, 119.52, 124.01, 129.01, 129.91, 130.76, 141.08, 156.38, 161.20, 162.13, 163.33, 164.91, 171.84, 175.85; LC-MS (retention time: 1.67, method B), MS m / z 679 (M ⁺ +1). HRMS m / z (M + H) ⁺ C ₃₅ H ₄₃ N ₄ SO ₈ : Calculated value 679.2802, Actual value 679.2805.

Step 4c: (1R, 2R of (4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carboxylic acid (1-cyclopropanesulfonylaminocarbonyl-2-ethylcyclopropyl) amide dihydrochloride ) Production of P1 isomers (below)

A solution of 1.50 g (2.20 mmol) of the product of step 4b in 125 mL of 4N HCl in dioxane was stirred for 2.5 h. The mixture was concentrated in vacuo to ˜2 mL and 30 mL Et ₂ O was added. The resulting precipitate was filtered and the white solid was dried overnight under high vacuum (40 ° C., 1 torr) to give 1.424 g (99%) of the title compound. ¹ H NMR (methanol d ₄ ) δ 0.97−1.75 (m, 13H), 2.27−2.36 (m, 1H), 2.53−2.61 (m, 1H), 2.92−3.01 (m, 1H), 4.07 (s, 3H ), 3.87−4.30 (m, 2H), 6.01 (m, 1H), 7.48 (dm, J = 8.0 Hz, 1H), 7.62-7.79 (m, 5H), 8.13 (d, J = 3.1 Hz, 1H) , 8.57 (d, J = 9.1 Hz, 1H); ¹³ C NMR (CD ₃ 0D, rotamer) δ 6.02, 6.48, 6.56, 13.89, 21.22, 22.69, 32.00, 33.11, 33.86, 37.10, 41.63, 52.86, 57.14, 60.46, 81.18, 100.68, 102.44, 116.11, 122.13, 126.93, 130.22, 130.85, 133.27, 134.01, 143.82, 158.35, 162.72, 167.31, 170.26, 171.15; LC-MS (retention time: 1.23, method B), MS m / z 579 (M ⁺ +1). HRMS m / z (M + H) ⁺ : C ₃₀ H ₃₅ SN ₄ 0 ₆ : Calculated value 579.2277, Actual value 579.2250.

Step 4d: Production of Compound 2
To a solution of the product of step 4c (100 mg, 0.154 mmol) in 2 mL CH ₂ Cl _{2 was} added BOC-L-tert-leucine 53.2 mg (0.23 mmol), HOAT 31.3 mg (0.23 mmol), HATU 87.5. mg (0.23 mmol) and DIPEA 161 μL (0.92 mmol) were added. The mixture was stirred for 1 day and partitioned between 100 mL of EtOAc and 50 mL of pH 4.0 buffer. The EtOAc layer was washed with brine (50 mL), dried (MgSO _4), and concentrated in vacuo. The residue was chromatographed on two Analtech 1000μ PTLC plates (each 20 × 40 cm, eluted with 2% MeOH in CH ₂ Cl ₂ ) to give 115 mg (94%) of foamy compound 2. It was. ¹ H NMR (methanol-d ₄ ) δ 0.90-1.08 (m, 2H), 0.96 (t, J = 7 Hz, 3H), 1.03 (s, 9H), 1.12-1.33 (m, 2H), 1.26 (s , 9H), 1.43-1.66 (m, 5H), 2.29-2.40 (m, 1H), 2.64 (dd, J = 14, 7 Hz, 1H), 2.85-3.02 (m, 1H), 3.93 (s, 3H ), 4.07−4.12 (m, 1H), 4.24−4.27 (m, 1H), 4.50−4.56 (m, 2H), 5.53 (m, 1H), 6.67 (d, J = 9.5 Hz, 1H), 7.06 (dd, J = 9.2, 2.2 Hz, 1H), 7.22 (s, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.46-7.56 (m, 3H), 8.03−8.07 (m, LC-MS (retention time: 1.52 method A), MS m / z 792 (M ⁺ +1). HRMS m / z (M + H) ⁺ C _4l H ₅₄ N ₅ O ₉ S calculated: 792.3642 , Actual value: 792.3654.

Example 5
Compound 3, {1- [2- (1-cyclopropanesulfonylaminocarbonyl-2-ethylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidin-1-carbonyl] -2 -Methylpropyl} The (1R, 2R) P1 isomer of carbamic acid tert-butyl ester (below) was prepared as follows.

To a solution of the product of Step 4c (700 mg, 1.074 mmol) in 14 mL of CH ₂ Cl ₂ , N-BOC-1-valine 350 mg (1.61 mmol), HOAT 219.3 mg (1.61 mmol), HATU613 mg (1.61 mmol) and 1.12 mL (6.45 mmol) of DIPEA were added. The mixture was stirred for 1 day and partitioned between 700 mL of EtOAc and 350 mL of pH 4.0 buffer. The EtOAc layer was washed with brine (350 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on a Biotage 40+ M column (eluting with 0% to 10% MeOH in CH ₂ Cl ₂ ) to give 800 mg of a slightly impure crude residue. Chromatography on Anaruteku manufactured by five 1000 [mu] PTLC plates (eluted in each 20X40 cm, CH ₂ C1 ₂ in 2% MeOH), compound 3 as a white solid 650 mg (78%) was obtained. LC / MS rt-min (MH ⁺ ): 1.45 (778) (Method A). HRMS m / z: (M + H) C ₄₀ H ₅₂ N ₅ SO ₉ : Calculated: 778.3486, Found: 778.3509. ¹ H NMR: (methanol-d ₄ , 300 MHz) δ 0.66−1.37 (m, 5H), 0.82 (d, = 7 Hz, 3H), 0.88 (t, J = 7, 3H), 1.05 (m, 12H), 1.61-1−1.81 (m, 3H), 2.07−2.43 (m, 3H), 2.55−2.67 (m, 1H), 2.79−3.10 (m, 1H), 3.82−3.87 (m, 1H), 3.91 (s, 3H ), 4.03 (d, J = 12 Hz, 1H), 4.12−4.17 (m, 1H), 4.49−4.55 (m, 1H), 5.28 (m, 1H), 6.82−6.94 (m, 2H), 7.38− 7.50 (m, 4H), 7.68−7.81 (m, 1H), 7.92−7.96 (m, 2H).

Example 6
Compound 4, (1- (2-amino-3-methylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2-carboxylic acid (1-cyclopropanesulfonylaminocarbonyl-2- The (1R, 2R) P1 isomer of ethylcyclopropyl) amide dihydrochloride (below) was prepared as follows.

A total of 600 mg of compound 3 was dissolved in 60 mL of 4N HCl / dioxane and stirred for 2.5 h. The slurry was concentrated to about 1 mL of solvent. 60 mL of Et ₂ O was added, the mixture was filtered, and the resulting solid was dried in vacuo overnight (50 ° C., 25 torr) to give 500 mg (86%) of compound 4 as a white solid. ¹ H NMR (methanol-d ₄ ) δ 0.99 (t, J = 7 Hz, 3H), 1.03-1.20 (m, 9H), 1.22-1.29 (m, 2H), 1.46-1.70 (m, 4H), 2.27 −2.37 (m, 1H), 2.42−2.51 (m, 1H), 2.78−2.83 (m, 1H), 2.93−3.03 (m, 1H), 4.06 (s, 3H), 4.15−4.26 (m, 2H) , 4.48 (d, J = 13 Hz, 1H), 4.71−4.76 (m, 1H), 5.92 (m, 1H), 7.45−7.48 (m, 1H), 7.59 (d, J = 2 Hz, 1H), 7.63 (s, 1H), 7.70-7.77 (m, 3H), 8.10, 8.10 (2s, 2H), 8.41 (d, J = 9 Hz, 1H); LC-MS (retention time: 1.10 method A), MS m / z 677 (M ⁺ +1).

Example 7
Compound 5, 1- [2- (2-cyclopropylacetylamino) -3-methylbutyryl] -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carboxylic acid (1-cyclopropanesulfonyl) The (1R, 2R) Pl isomer of aminocarbonyl-2-ethylcyclopropyl) amide (below) was prepared as follows.

To a solution of 85 mg (0.113 mmol) of compound 4, DIPEA 119 μL (0.68 mmol), HOAT 23.1 mg (0.17 mmol) and cyclopropylacetic acid 17 mg (0.17 mmol) in 2 mL of CH ₂ Cl ₂ , HATU 64.6 mg (0.17 mol) was added. The mixture was stirred for 18 h and partitioned between 100 mL EtOAc and 35 mL pH 4.0 buffer. The EtOAc layer was washed with brine (35 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was Anaruteku manufactured by one 20X40 cm, chromatographed 1000 [mu] PTLC plates (eluted with CH ₂ C1 ₂ in 2% MeOH), to give the compound 5 foamy 63 mg (73%). ¹ H NMR (methanol-d ₄ ) δ 0.07-0.10 (m, 2H), 0.37-0.44 (m, 2H), 0.80-0.86 (m, 1H), 0.94-0.97 (m, 6H), 1.00 (d, J = 7 Hz, 3H), 1.05−1.10 (m, 2H), 1.16−1.21 (m, 2H), 1.25−1.30 (m, 1H), 1.50−1.57 (m, 2H), 1.60−1.65 (m, 2H), 1.93−2.01 (m, 2H), 2.15−2.22 (m, 1H), 2.33−2.38 (m, 1H), 2.61 (dd, J = 14, 6.6 Hz, 1H), 2.93−2.98 (m, 1H), 3.94 (s, 3H), 4.13 (dd, J = 12, 3.5 Hz, 1H), 4.44 (t, J = 9 Hz, 1H), 4.49−4.56 (m, 2H), 5.60 (m, 1H ), 7.12 (dd, J = 9.1, 2.4 Hz, 1H), 7.27 (s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.50−7.55 (m, 3H), 7.91 (d, J = 9 Hz, 1H), 8.04-8.05 (m, 3H); LC-MS (retention time: 1.51 method A), MS m / z 786 (M ⁺ +1). HRMS m / z (M + H) ⁺ C ₄₀ H ₅₀ N ₅ 0 ₈ S Calculated: 760.3380, Actual: 760.3398.

Example 8
Compound 6, 1- [2- (1-cyclopropanesulfonylaminocarbonyl-2-ethylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-1-carbonyl] -2- The (1R, 2R) Pl isomer of methylpropyl} -carbamic acid cyclopentyl ester (below) was prepared as follows.

To a solution of 85 mg (0.113 mmol) of compound 4, DIPEA 119 μL (0.68 mmol) in 2 mL of CH ₂ Cl _2, 400 μL (0.27 mol) of cyclopentyl chloroformate accurately measured in THF (Example 21, Step 21a) Prepared in the same manner as the chloroformate used in 1). The mixture was stirred for 18 h and the EtOAc layer was washed with brine (35 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was Anaruteku manufactured by one 20X40 cm, chromatographed 1000 [mu] PTLC plates (eluted with CH ₂ C1 ₂ in 2% MeOH), P4 (cyclopentyl -O (C = O)) N -P3 (L- Val) -P2 [(4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) proline] -P1 (1R, 2R ethyl Acca) -CONHSO ₂ cyclopropane, {1- [2- (1- Cyclopropanesulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1-carbonyl] -2-methylpropyl} carbamic acid cyclopentyl ester 71 mg (79%) was obtained as a foam. ¹ H NMR (methanol-d ₄ , rotamer ~ 1/1) δ 0.80-1.80 (m, 26H), 2.04−2.22 (m, 1H), 2.24−2.39 (m, 1H), 2.61−2.69 (m , 1H), 2.95 (m, 1H), 3.94 (s, 3H), 4.04−4.12 (m, 2H), 4.53−4.65 (m, 3H), 5.51−5.57 (m, 1H), 7.11 (d, J = 8 Hz, 1H), 7.21−7.25 (m, 1H), 7.39−7.40 (m, 1H), 7.49−7.56 (m, 3H), 8.03−8.09 (m, 3H); LC-MS (retention time: 1.69, Method D), MS m / z 816 (M ⁺ +1). HRMS m / z (M + H) ⁺ C ₄₁ H ₅₂ N ₅ O ₉ S Calculated: 790.3486, Found: 790.3479.

Example 9
Compound 7, 1- [2- (1-cyclopropanesulfonylaminocarbonyl-2-ethylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-1-carbonyl] -2- The (1R, 2R) Pl isomer of methyl-propyl} carbamic acid ethyl ester (below) was prepared as follows.

To a solution of 85 mg (0.113 mmol) of compound 4, DIPEA 119 μL (0.68 mmol) in 2 mL of CH ₂ Cl ₂ was added exactly 27 μL (0.27 mol) of ethyl chloroformate (Aldrich). The mixture was stirred for 18 h and partitioned between 100 mL of EtOAc and 35 mL of pH 4.0 buffer. The EtOAc layer was washed with brine (35 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue subjected Anaruteku manufactured by one 20X40 cm, chromatographed 1000 [mu] PTLC plates (eluted with CH ₂ C1 ₂ in 2% MeOH), to give compound 766 mg (78%) as a white solid. ¹ H NMR (methanol-d ₄ ) δ 0.70 (t, J = 7 Hz, 3H), 0.88-1.34 (m, 15H), 1.46-1.80 (m, 4H), 2.07-2.38 (m, 2H), 2.46 (m, 1H), 2.58−2.62 (m, 1H), 3.66−3.81 (m, 2H), 3.88 (s, 3H), 4.05−4.13 (m, 1H), 4.21 (s, 1H), 4.54 (dd , J = ll, 6 Hz, 1H), 4.60 (dd, J = ll. 6 Hz, 1H), 5.49, 5.52 (m, 1H), 6.57 (d, J = 8 Hz, NH), 7.20 (s, 1H), 7.35 (s, 1H), 7.47-7.55 (m, 4H), 7.74 (d, J = 9 Hz, 1H), 8.02-8.05 (m, 3H); LC-MS (retention time: 1.39; method A), MS m / z 750 (M ⁺ +1). HRMS m / z (M + H) ⁺
C ₃₈ H ₄₈ N ₅ O ₉ S Calculated value: 750.3173, Actual value: 750.3172.

Example 10
Compound 8, 4- (7-methoxy-2-phenylquinolin-4-yloxy) -1- [3-methyl-2- (3-propylureido) butyryl] pyrrolidine-2-carboxylic acid (1-cyclopropanesulfonylamino) The (lR, 2R) Pl isomer of carbonyl-2-ethyl-cyclopropyl) amide (below) was prepared as follows.

To a solution of 85 mg (0.113 mmol) of compound 4, DIPEA 119 μL (0.68 mmol) in 2 mL of CH ₂ Cl ₂ was added exactly 27 μL (0.27 mol) of N-propyl isocyanate (Aldrich). The mixture was stirred for 18 h and partitioned between 100 mL EtOAc and 35 mL pH 4.0 buffer. The EtOAc layer was washed with brine (35 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue subjected Anaruteku manufactured by one 20X40 cm, chromatographed 1000 [mu] PTLC plates (eluted with CH ₂ C1 ₂ in 2% MeOH), to give 74 mg of compound 8 (85%) as a foam. ¹ H NMR (MeOD) δ 0.81 (t, J = 7 Hz, 3H), 0.88−1.68 (m, 20H), 2.05−2.14 (m, 1H), 2.32−2.38 (m, 1H), 2.58−2.62 ( m, 1H), 2.87−2.99 (m, 3H), 3.93 (s, 3H), 4.09−4.12 (m, 1H), 4.24−4.27 (m, 1H), 4.50−4.54 (m, 2H), 5.55 ( m, 1H), 6.01 (d, J = 9 Hz, NH), 7.09 (dd, J = 9.1, 2.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.47−7.52 (m , 3H), 8.02−8.04 (m, 2H), 8.06 (d, J = 9.1 Hz, 1H); LC-MS (retention time: 1.38, method A), MS m / z 763 (M ⁺ +1 HRMS m / z (M + H) ⁺ C ₃₉ H ₅₁ N ₆ 0 ₈ S Calculated: 763.3489, Found: 763.3477.

Example 11
Compound 9, 1- [2- (1-cyclopropanesulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-1-carbonyl] -2 -Methylpropyl} The (1R, 2R) P1 isomer of carbamic acid 2-fluoroethyl ester (below) was prepared as follows.

To a solution of 85 mg (0.113 mmol) of compound 4, DIPEA 119 μL (0.68 mmol) in 2 mL of CH ₂ Cl ₂ was added precisely measured 32 μL (0.27 mol) of 2-fluoroethyl chloroformate (Aldrich). . The mixture was stirred for 18 h and partitioned between 100 mL EtOAc and 35 mL pH 4.0 buffer. The EtOAc layer was washed with brine (35 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue subjected Anaruteku manufactured by one 20X40 cm, chromatographed 1000 [mu] PTLC plates (eluted with CH ₂ C1 ₂ in 2% MeOH), to give the compound 9 of 63 mg (72%) as a white solid. ¹ H NMR (methanol-d ₄ ) δ 0.75-1.23 (m, 14H), 1.26-1.33 (m, 1H), 1.55-1.83 (m, 4H), 2.10-2.36 (m, 3H), 2.48 (m, 1H), 2.54−2.64 (m, 1H), 3.83 (s, 3H), 3.78−4.64 (m, 8H), 5.49 (m, 1H), 6.64 (m, NH), 7.18 (s, 1H), 7.29 (s, 1H), 7.46-7.54 (m, 4H), 7.74 (d, J = 9 Hz, 1H), 8.04-8.05 (m, 3H); LC-MS (retention time: 1.33, method A), MS m / z 768 (M ⁺ +1). HRMS m / z (M + H) + C ₃₈ H ₄₇ FN ₅ 0 ₉ S Calculated: 768.3079, Found: 768.3091.

Example 12
1-{[1-2-tert-butoxycarbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carbonyl] amino} -2- The (lR, 2S) P1 isomer of vinylcyclo-propanecarboxylic acid (below) was prepared as described in steps 12a-e.

Step 12a: Preparation of (lR, 2S) / (1S, 2R) -1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride (below)

The title compound was prepared by each of Methods A and B below.
Method A
A. 1) Production of N-benzylimine (below) of glycine ethyl ester

Glycine ethyl ester hydrochloride (303.8 g, 2.16 mole) was suspended in tert-butyl methyl ether (1.6 L). Benzaldehyde (231 g, 2.16 mole) and anhydrous sodium sulfate (154.6 g, 1.09 mole) were added and the mixture was cooled to 0 ° C. using an ice-water bath. Triethylamine (455 mL, 3.26 mole) was added dropwise over 30 min and the mixture was stirred for 48 h at rt. The reaction was terminated by the addition of ice-cold water (1 L) and the organic layer was separated. The aqueous phase was extracted with tert- butyl methyl ether (0.5 L), the organic layers were combined and washed with a mixture of saturated aqueous NaHC0 ₃ (1 L) and brine (1 L). The solution was dried over MgSO ₄ and concentrated in vacuo to give 392.4 g of the N-benzylimine product as a dark yellow oil that was used directly in the next step. ¹ H NMR (CDC1 ₃ , 300 MHz) δ 1.32 (t, J = 7.1 Hz, 3H), 4.24 (q, J = 7.1 Hz, 2H), 4.41 (d, J = l.1 Hz, 2H), 7.39 −7.47 (m, 3H), 7.78−7.81 (m, 2H), 8.31 (s, 1H).

A. 2) Preparation of N-Boc- (1R, 2S) / (1S, 2R) -1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester racemate

  To a suspension of (1.2 L) lithium tert-butoxide (84.06 g, 1.05 mol) in dry toluene was added N-benzylimine (100.4 g, 0.526 mol) of glycine ethyl ester and trans-1 in dry toluene (0.6 L). , 4-Dibromo-2-butene (107.0 g, 0.500 mol) was added dropwise over 60 min. After the reaction was complete, the crimson mixture was terminated by adding water (1 L) and tert-butyl methyl ether (TBME, 1 L). The aqueous phase was separated and extracted a second time with TBME (1 L). The organic phases were combined, 1 N HCl (1 L) was added and the mixture was stirred at room temperature for 2 h. The organic phase was separated and extracted with water (0.8 L).

The aqueous phases were then combined, saturated with brine (700 g), TBME (1 L) was added and the mixture was cooled to 0 ° C. The stirred mixture was then added dropwise with 10 N NaOH to make it pH 14 alkaline, the organic layer was separated and the aqueous phase was extracted with TBME (2 × 500 mL). Dry the organic extracts were washed with (MgSO _4), and concentrated to a volume 1L. To this solution of free To this solution of free amine was added di-tert-butyl dicarbonate (131.0 g, 0.6 mol) and the mixture was stirred at rt for 4 days. Further di-tert-butyl dicarbonate (50 g, 0.23 mol) was added to the reaction and the mixture was refluxed for 3 h then allowed to cool to room temperature overnight. The reaction mixture was dried over MgSO _4, and concentrated in vacuo to give the crude material 80 g. The residue was purified by flash chromatography (eluted with 2.5 Kg of SiO ₂ , 1% to 2% MeOH / CH ₂ Cl ₂ ), and N-Boc- (1R, 2S) / (1S, 2R) -1- A racemic 57 g (53%) of amino-2-vinylcyclopropanecarboxylic acid ethyl ester was obtained as a yellow oil, which was left in the refrigerator to form a solid. _{^{1 H NMR (CDC1 3, 300}} MHz) δ 1.26 (t, J = 7.1 Hz, 3H), 1.46 (s, 9H), 1.43-1.49 (m, 1H), 1.76-1.82 (br m, 1H), 2.14 (q, J = 8.6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 5.12 (dd, J = 10.3, 1.7 Hz, 1H), 5.25 (br s, 1H), 5.29 (dd , J = 17.6, 1.7 Hz, 1H), 5.77 (ddd, J = 17.6, 10.3,8.9 Hz, 1H); MS m / z 254.16 (M ⁺ −1).

A.3 Preparation of racemic (1R, 2S) / (1S, 2R) 1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride

N-Boc- (1R, 2S / 1S, 2R) -1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester (9. 39 g, 36.8 mmol) dissolved in 4N HCl / dioxane (90 ml, 360 mmol) And stirred for 2 h at rt. The reaction mixture was concentrated to give (1R, 2S / 1S, 2R) -1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride in quantitative yield (7 g, 100%). ¹ H NMR (methanol-d ₄ ) δ: 1.32 (t, J = 7.1, 3H), 1.72 (dd, J = 10.2, 6.6 Hz, 1H), 1.81 (dd, J = 8. 3, 6.6 Hz, 1H ), 2.38 (q, J = 8.3 Hz, 1H), 4.26−4.34 (m, 2H), 5.24 (dd, 10.3, 1.3 Hz, 1H) 5.40 (d, J = 17.2,1H), 5.69−5.81 (m, 1H).

THF(450 mL)中カリウムtert−ブトキシド(11.55 g, 102.9 mmol)の溶液に、−78℃にて、THF(112 mL)中市販のグリシンエチルエステルのＮ,Ｎ−ジベンジルイミン(25.0 g, 93.53 mmol)を添加した。反応混合物を０℃に温め、40 min間攪拌し、ついで、−78℃に再度冷却した。この溶液にトランス−１,４−ジブロモ−２−ブテン(20.0 g, 93.50 mmol)を添加し、混合物を1 h、０℃にて攪拌し、−78℃に再度冷却した。カリウムtert−ブトキシド(11.55 g, 102.9 mmol)を添加し、混合物を直ぐに０℃に温め、さらに１時間攪拌し、真空にて濃縮した。粗生成物をEt₂O(530 mL)に取り、1N HCl水溶液(106 mL, 106 mmol)を添加し、得られた２層の混合物を3.5 h、rtにて攪拌した。層を分離し、水層をEt₂O(2x)で洗滌し、飽和NaHC0₃水溶液で塩基性にした。所望のアミンをＥt₂Ｏ(3x)で抽出し、一緒にした有機抽出物を食塩水で洗滌し、乾燥させ(ＭgＳＯ₄)、真空にて濃縮し、遊離のアミンを得た。この物質をジオキサン(100 mL, 400 mmol)中4N HCl溶液で処理し、濃縮し、(lR,2S)／(1S,2R)−１−アミノ−２−ビニルシクロプロパン カルボン酸エチルエステル塩酸塩(5. 3 g, 34%収率)を固体褐色の半固体として得、少量の未確認芳香族不純物(8%)が存在するが、方法Ａから得られた物質に一致した。 Method B

To a solution of potassium tert-butoxide (11.55 g, 102.9 mmol) in THF (450 mL) at −78 ° C., commercially available N, N-dibenzylimine (25.0 g, 93.53 mmol) was added. The reaction mixture was warmed to 0 ° C., stirred for 40 min, and then cooled again to −78 ° C. To this solution was added trans-1,4-dibromo-2-butene (20.0 g, 93.50 mmol) and the mixture was stirred for 1 h at 0 ° C. and cooled again to −78 ° C. Potassium tert-butoxide (11.55 g, 102.9 mmol) was added and the mixture was immediately warmed to 0 ° C., stirred for an additional hour and concentrated in vacuo. The crude product was taken up in Et ₂ O (530 mL), 1N aqueous HCl (106 mL, 106 mmol) was added, and the resulting two-layer mixture was stirred at rt for 3.5 h. The layers were separated and the aqueous layer was washed with Et ₂ O (2x), basified with saturated NaHCO ₃ aq. The desired amine was extracted with Et ₂ O (3 ×) and the combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the free amine. This material was treated with 4N HCl solution in dioxane (100 mL, 400 mmol), concentrated and (lR, 2S) / (1S, 2R) -1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride ( 5.3 g, 34% yield) was obtained as a solid brown semi-solid, with a small amount of unidentified aromatic impurities (8%), consistent with the material obtained from Method A.

Step 12b: (1R, 2S of 2- (l-ethoxycarbonyl-2-vinylcyclopropylcarbamyl-4- (7-methoxyl-2-phenylquinolin-4-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester ) Production of P1 isomers (below)

Boc-4 (R)-(2-phenyl-7-methoxyquinoline-4-oxo) proline from step 1c (11.0 g, 23.7 mmole) in 500 mL 50% CH ₂ Cl ₂ / THF, from step 11b ( HCl salt of a racemic mixture of (R, 2S) and (1S, 2R) P1 derived diastereomers, where the carboxy group is syn to the vinyl group (5.40 g, 28.2 mmole), NMM (20.8 mL; 18.9 mmole) The coupling reagent PyBrop, ie, bromotrispyrrolidino-phosphonium hexafluorophosphate (16.0 g, 34.3 mmole), was added in 3 portions at 0 ° C. over 10 min. The solution was stirred at rt for 1 day and then washed with pH 4.0 buffer (4 × 50 mL). The organic layer was washed with saturated aqueous NaHC0 ₃ (100 mL), the aqueous washings were extracted with ethyl acetate (150 mL), the organic layer again pH 4.0 buffer (50 mL) and saturated aqueous NaHCO ₃ (50 mL) Washed with. The organic solution was dried (MgSO ₄ ), concentrated and purified using a Biotage 65M column (eluting with 50% EtOAc / hexanes) to give (s of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamyl- 7.5 g of a 1: 1 mixture of (1R, 2S) and (1S, 2R) P1 isomers of 4- (7-methoxyl-2-phenylquinolin-4-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (50% overall yield) or alternatively, slowly elute on a Biotage 65M column using a 15% to 60% EtOAc gradient in hexanes and high Rf eluate (1R, 2S) P1 isomerism 3.54 g (25%) of the product and 3.54 g (25%) of the low Rf eluate (1S, 2R) P1 isomer were obtained.

(1R, 2S) Pl isomer data: ¹ H NMR (CDCl ₃ ) δ 1.21 (t, J = 7 Hz, 3H), 1.43 (s, 9H), 1.47–1.57 (m, 1H), 1.88 (m , 1H), 2.05−2.19 (m, 1H), 2.39 (m, 1H), 2.88 (m, 1H), 3.71−3.98 (m, 2H), 3.93 (s, 3H), 4.04−4.24 (m, 2H ), 4.55 (m, 1H), 5.13 (d, J = 10 Hz, 1H), 5.22−5.40 (m, 1H), 5.29 (d, J = 17 Hz, 1H), 5.69−5.81 (m, 1H) , 7.02 (brs, 1H), 7.09 (dd, J = 9,2 Hz, 1H), 7.41−7.52 (m, 4H), 7.95 (d, J = 9 Hz, 1H), 8.03, 8.05 (2s, 2H ); ¹³ C NMR (CDC1 ₃ ) δ: 14.22; 22.83, 28.25, 33.14, 33.58, 39.92, 51.84, 55.47, 58.32, 61.30, 75.86, 81.27, 98.14, 107.42, 115.00, 117.84, 118.27, 122.63, 123.03, 127.50 , 128.72, 129.26, 133.39, 140.06, 151.23, 159.16, 160.34, 161.35, 169.78, 171.68. LC-MS (retention time: 1.62, method D), MS m / z 602 (M ⁺ +1).

(1S, 2R) P1 isomer data: ¹ H NMR δ 1.25 (t, J = 7 Hz, 3H), 1.44 (s, 9H), 1.46−1.52 (m, 1H), 1.84 (m, 1H), 2.12−2.21 (m, 1H), 2.39 (m, 1H), 2.94 (m, 1H), 3.82 (m, 2H), 3.97 (s, 3H), 4.05−4.17 (m, 2H), 4.58 (m, 1H), 5.15 (d, J = 10.8 Hz, 1H), 5.33 (d, J = 17 Hz, 1H), 5.30−5.43 (m, 1H), 5.72−5.85 (m, 1H), 7.05 (s , 1H), 7.13 (dd, J = 9,2 Hz, 1H), 7.46−7.60 (m, 4H), 7.98 (d, J = 9, 1H), 8.06−8.10 (m, 2H). LC-MS (Retention time: 1.66, Method D), MS m / z 602 (M ⁺ +1).

Step 12c: 1-{[4- (7-Methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carbonyl] -1-amino} -2-vinylcyclopropanecarboxylic acid ethyl ester dihydrochloride ( 1R, 2S) Production of P1 diastereomers (below)

The product of step 12b (5.88 g, 9.77 mmol) was dissolved in HCl / dioxane (4. OM; 200 ml) and stirred at rt for 2.5 h. The reaction mixture was concentrated to give the title compound. ¹ H NMR (methanol-d ₄ ) δ 1.24 (t, J = 7 Hz, 3H), 1.50 (dd, J = 10, 5 Hz, 1H), 1.78 (dd, J = 8.4, 5.5 Hz, 1H ), 2.24−2.33 (m, 1H), 2.56−2.66 (m, 1H), 3.05 (dd, J = 14.6, 7.3 Hz, 1H), 3.98 (s, 2H), 4.06 (s, 3H), 4.15 (q, J = 7 Hz, 2H), 4.76 (dd, J = 10. 6, 7.3 Hz, 1H), 5.13 (dd, J = 10. 2, 1.8 Hz), 5.32 (dd, J = 17, 2 Hz), 5.70−5.83 (m, 1H), 6.05 (m, 1H), 7.48 (dd, J = 9, 2 Hz, 1H), 7.65−7.79 (m, 5H), 8.12−8.15 (m, 2H ), 8.54 (d, J = 9.5 Hz, 1H); ¹³ C NMR (methanol-d ₄ ) δ: 14.77, 23.23, 34.86, 37.25, 41.19, 43.90, 52.66, 60.35, 62.32, 62.83, 68.27, 72.58 , 73.70, 81.21, 100.70, 102.44, 116.13, 118.67, 122.25, 126.93, 130.27, 130.94, 133.19, 134.14, 134.89, 143.79, 158.39, 166.84, 167.44, 169.57, 171.33.LC-MS (retention time: 1.55, method D ), MS m / z 502 (M ⁺ +1)

Step 12d: 1-{[1-2-tert-Butoxy-carbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) p-pyrrolidine-2-carbonyl ] -Amino} -2-vinyl-cyclopropanecarboxylic acid ethyl ester (1R, 2S) P1 isomer production

To a suspension of step 12c (1.95 g; 3.4 mmol), N-Boc-1-tert-leucine (0.94 g, 4.08 mmol), NMM (1.87 ml, 17 mmol) in DMF (15 mL), HATU (1.55 g, 4.08 mmol) was added at 0 ° C. After stirring for 2 days, the reaction mixture was diluted with EtOAc (200 mL), washed with pH 4.0 buffer (2 × 30 mL), saturated aqueous NaHCO ₃ (30 mL), brine (30 mL) and dried (MgSO ₄ ). Purification on a Biotage 40 M column (eluting with 15% to 60% EtOAc in hexanes) gave the title compound as a white solid (2.21 g, 90%). ¹ H NMR (CDC1 ₃ ) δ 1. 05 (s, 9H), 1.20 (t, J = 7 Hz, 3H), 1.38−1.43 (m, 1H), 1.41 (s, 9H), 1.80−1.85 (m , 1H), 2.08−2.16 (m, 1H), 2.39−2.47 (m, 1H), 2.90−2.99 (m, 1H), 3.90−4.01 (m, 1H), 3.93 (s, 3H) , 4.12 (q, J = 7 Hz, 2H), 4.36 (d, J = 10 Hz, 1H), 4.45 (d, J = 12 Hz, 1H), 4.75−4.85 (m, 1H), 5.09−5.13 ( m, 1H), 5.21−5.34 (m, 2H), 5.69−5.81 (m, 1H), 7.00−7.09 (m, 2H), 7.42−7.54 (m, 5H), 8.01−8.05 (m, 3H); ¹³ C NMR (CDC1 ₃ ) δ 14.30, 22.85, 26.40, 28.25, 32.20, 34.09, 35.39, 39.97, 53.86, 55.47, 58.28, 58.96, 61.29, 75.94, 79.86, 97.98, 107.43, 115.06, 117.98, 118.38, 123.03, 127.52, 128.76, 129.24, 133.40, 140.26, 151.44, 155.74, 159.16, 160.09, 161.32, 169.55, 170.64, 172.63.LC-MS (retention time: 1.85, method D), MS m / z 715 (M ⁺ + l) .

Step 12e: Title compound, 1-([1-2-tert-butoxycarbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carbonyl Preparation of (lR, 2S) Pl isomer of amino} -2-vinylcyclo-propanecarboxylic acid
To a suspension of the product of step 12d (2.63 g, 3.68 mmol) in THF (150 mL), CH ₃ OH (80 mL) and H ₂ O (20 mL) was added LiOH (1.32 g, 55.2 mmol). did. The reaction mixture was stirred for 2 days, acidified to neutral pH and concentrated in vacuo, leaving only the aqueous layer. The resulting aqueous residue was acidified to pH 3.0 by addition of 1.0 N aqueous HCl and extracted with EtOAc (4 × 200 mL). The combined organic solvents were washed with brine (20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound as a white solid (2.41 g, 96%). ¹ H NMR (CDCl ₃ / methanol-d ₄ ) δ 0.98, 1.01 (2 s (rotamers) 9H), 1.40, 1.42 (2 s (rotamers) 9H), 1.35–1.47 (m , 1H), 1.89−1.93 (m, 1H), 2.03−2.14 (m, 1H), 2.45−2.52 (m, 1H), 2.64−2.78 (m, 1H), 3.94 (s, 3H), 3.96−4.12 (m, 1H), 4.34 (d, J = 10 Hz, 1H), 4.52 (d, J = ll Hz, 1H), 4.58−4.64 (m, 1H), 5.10 (d, J = 12 Hz, 1H) , 5.24 (d, J = 16 Hz, 1H), 5.34 (m, 1H), 5.68−5.86 (m, 2H), 7.02−7.05 (m, 1H), 7.32 (m, 1H), 7.40−7.54 (m , 4H), 7.97-8.03 (m, 3H); LC-MS (retention time: 1.64, method D), MS m / z 687 (M ⁺ +1).

  The hydrolysis method described in step 12e of this specification can be used for all vinyl Acca-containing N-BOC tripeptides such as the product of step 12d.

Example 13
Compound 10, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline] -P1 (lR, 2S vinyl Acca) -CONHSO ₂ -cyclopropane, also known as {1- [2- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine- The (1R, 2S) P1 diastereomer of 1-carbonyl] -2,2-dimethylpropyl} carbamic acid tert-butyl ester (below) was prepared as described in Steps 13a-b.

Step 13a: Preparation of cyclopropyl sulfonamide

Ammonia gas was bubbled into a solution of 100 mL of THF cooled to 0 ° C. until saturation. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array BiopHarma) in 50 mL of THF and the solution was warmed at rt overnight and stirred for another day. The mixture was concentrated until the solvent remained 1-2 mL, subjected to Si0 ₂ of plug 30 g (eluted 30% in 60% EtOAc / hexane) to give a white solid of cyclopropyl sulfonamide 3.45g (100%) . ¹ H NMR (methanol-d ₄ ) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); ¹³ C NMR (methanol-d ₄ ) δ 5.92, 33.01.

Step 13b: Production of Compound 10
To a solution of CDI (0.238 g, 1.47 mmol) in THF (3 mL), a solution of the product of step 12e (0.837 g, 1.22 mmol) in THF (20 mL) was added dropwise under a 10 min stream of argon. . The resulting solution was stirred for 30 min, refluxed for 30 min and allowed to cool to rt. Cyclopropylsulfonamide (0.591 g, 4.88 mmol) was added in one portion and a solution of DBU (0.36 mL, 2.44 mmol) in THF (2 mL) was added. The reaction was stirred for 18 h, diluted with EtOAc (200 mL), washed with pH 4.0 buffer (3 × 30 mL), water (2 × 30 mL), brine (30 mL), dried (MgSO ₄ ), Biotage 40 M column. (Elution with 0% to 5% MeOH in CH ₂ Cl ₂ ) afforded opaque glassy compound 10 (0.48 g, 500). ¹ H NMR (methanol-d ₄ ) δ 0.80-1.10 (m, 2H), 1.03 (s, 9H), 1.17 (s, 2H), 1.27 (s, 9H), 1.38-1.41 (m, 1 H), 1.83−1.85 (m, 1H), 2.15−2.20 (m, 1H), 2.35−2.40 (m, 1H), 2.60−2.70 (m, 1H), 2.84 (bs, 1H), 3.93 (s, 3H), 4.08−4.10 (m, 1H), 4.25 (s, 1H), 4.50−4.55 (m, 2H), 5.07 (d, J = 10. 1 Hz, 1H), 5.25 (d, J = 17. 1 Hz, 1H), 5.53 (m, 1H), 5.77−5.84 (m, 1H), 7.05−7.07 (m, 1H), 7.23 (s, 1H), 7.37 (d, J = 2 Hz, 1H), 7.47−7.55 (m, 3H), 8.04-8.07 (m, 3H); LC-MS (retention time: 1.55, method A), MS m / z 790 (M ⁺ +1). HRMS m / z (M + H) ⁺ C _4l H ₅₂ N ₅ SO ₉ Calculated: 790.3486, Found 790.3505.

  This coupling method can be used to make N-acylsulfonamides of tripeptides containing either vinyl Acca or ethyl Acca P1 parts.

Example 14
Compound 11, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 (lR, 2S vinyl Acca)- BOCNH-2-cyclobutane, ie, {1- [2- (l-cyclobutanesulfonylaminocarbonyl-2-vinylcyclo-propylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine The (lR, 2S) P1 diastereomer of (-1-carbonyl] -2,2-dimethylpropyl} carbamic acid tert-butyl ester (below) was prepared as described in Steps 14a-b.

Step 14a: Preparation of cyclobutyl sulfonamide

To a solution of 5.0 g (37.0 mmol) of cyclobutyl bromide in 30 mL of anhydrous diethyl ether (Et ₂ O) cooled to −78 ° C. was added 44 mL (74.8 mmol) of 1.7M tert-butyllithium in pentane, and this solution Was slowly warmed to −35 ° C. over 1.5 h. The mixture was added through a tube to a solution of 5.0 g (37.0 mmol) of freshly distilled sulfuryl chloride in 100 mL of hexane cooled to −40 ° C., warmed to 0 ° C. over 1 h and carefully concentrated in vacuo. The mixture was redissolved in Et ₂ 0, once significant ice - washed with cold water, dried (MgSO ₄₎ and concentrated carefully. This mixture was redissolved in 20 mL of THF and added dropwise to 500 mL of saturated NH ₃ in THF and left to stir overnight. The mixture was concentrated in vacuo to give a crude product as a yellow solid that was recrystallized from CH ₂ Cl _{2 in} hexane with a minimum of 1-2 drops of MeOH to give 1.90 g (38 of cyclobutylsulfonamide as a white solid). %). ¹ H NMR (CDCl ₃ ) δ 1.95-2.06 (m, 2H), 2.30-2.54 (m, 4H), 3.86 (p, J = 8 Hz, 1H), 4.75 (brs, 2H); ¹³ C NMR (CDC1 _{. 3) δ 16.43, 23.93,} 56.29 HRMS m / z (M-H) - C 4 H 8 NS0 2 calculated: 134.0276, Found 134.0282.

Step 14b: Preparation of Compound 11 According to the method of Step 13b, the product of Step 12e, 100 mg (0.146 mmol), 33.1 mg (0.20 mmol) CDI, cyclobutylsulfonamide 27.6 mg (0.20 mmol) and DBU 31 μL Reaction with (0.20 mmol) gave 84.1 mg (72%) of foamy compound 11. LC / MS rt-min (MH ⁺ ): 1.62 (804) (Method D). ¹ H NMR: (Methanol-d ₄ , 300 MHz) δ 1.03, 1.04 (2s, 9H), 1.27, 1.30 (2s, 9H) , 1.33-1.43 (m, 1H), 1.80-2.50 (m, 11H), 2.66-2.80 (m, 1H), 3.71-3.88 (m, 1H), 3.92, 3.94 (2s, 3H), 4.00-4.13 ( m, 2H), 4.51−4.59 (m, 2H), 4.97−5.04 (m, 1H), 5.54 (m, 1H), 5.74−5.92 (m, 1H), 7.24 (s, 1H), 7.36− 7.38 (m, 1H), 7.45-7.55 (m, 3H), 8.04-8.11 (m, 3H).

Example 15
Compound 12, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 (lR, 2S vinyl Acca)- CONHS0 ₂ cyclopentane, also known as (1- [2- (1-cyclopentanesulfonyl-amino-2- vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-yloxy) - pyrrolidine -1 -Carbonyl] -2,2-dimethylpropyl} The (1R, 2S) P1 diastereomer of carbamic acid tert-butyl ester (below) was prepared as described in steps 15a-b.

Step 15a: Preparation of cyclopentyl sulfonamide

A solution of 18.5 mL (37.0 mmol) of 2M cyclopentylmagnesium chloride in ether was added dropwise to a solution of 3.0 mL (37.0 mmol) of sulfuryl chloride (obtained from Aldrich) in 100 mL of hexane cooled to -78 ° C. did. The mixture was warmed to 0 ° C. over 1 h and then carefully concentrated in vacuo. This mixture was redissolved in Et ₂ O (200 mL), washed with considerable ice-cold water (200 mL), dried (MgSO ₄ ) and carefully concentrated. This mixture was redissolved in 35 mL of THF and added dropwise to 500 mL of saturated NH ₃ in THF and left to stir overnight. The mixture was concentrated in vacuo to give a crude product as a yellow solid, the residue was filtered, passed through 50 g of silica gel using 70% EtOAc-hexane as eluent and then concentrated. The residue was recrystallized from CH ₂ Cl _{2 in} hexane with a minimum amount of 1-2 drops of MeOH to give 2.49 g (41%) of cyclopentylsulfonamide as a white solid. ¹ H NMR CDC1 ₃ ) δ 1.58-1.72 (m, 2H), 1.74-1.88 (m, 2H), 1.942.14 (m, 4H), 3.48-3.59 (m, 1H), 4.80 (bs, 2H); ¹³ C NMR (CDC1 ₃ ) δ: 25.90, 28.33, 63.54; MS m / e 148 (M−H) ⁻ .

Step 15b: Preparation of Compound 12 According to the method of Step 13b, the product of Step 12e, 60 mg (0.087 mmol), 19.8 mg (0.122 mmol) CDI, cyclopentylsulfonamide 18 mg (0.122 mmol) and DBU 18 μL (0.122 mmol). ) To obtain 45.1 mg (63%) of a foamy compound 12. ¹ H NMR (methanol-d ₄ ) δ 1.03 (s, 9H), 1.29 (s, 9H), 1.37-1.43 (m, 1H), 1.55-2.09 (m, 9H), 2.15-2.22 (m, 1H) , 2.29−2.39 (m, 1H), 2.63−2.70 (m, 1H), 3.43−3.53 (m, 1H), 3.94 (s, 3H), 4.04−4.15 (m, 1H), 4.23−4.30 (m, 1H), 4.47−4.57 (m, 2H), 5.08 (d, J = 10.2 Hz, 1H), 5.25 (d,
J = 16.5 Hz.1H), 5.52 (m, 1H), 5.70−5.80 (m, 1H), 6.54 (d, J = 9 Hz, 1H), 7.05 (dd, J = 9.2, 2.2 Hz.1H), 7.37 (d, J = 2.2 Hz, 1H), 7.45−7.55 (m, 3H), 8.00−8.06 (m, 3H). LC-MS (Retention time: 1.66, Method A). MS m / z 818 (M +1) ⁺ ; 816 (M−1) ^- .

Example 16
Compound 13, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 (lR, 2S vinyl Acca)- BOCNH-2-cyclohexane, also known as (lR, 2S) P1 diastereomer {1- [2- (l-cyclohexanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl) Quinolin-4-yloxy) pyrrolidine-1-carbonyl] -2,2-dimethylpropyl} carbamic acid tert-butyl ester (below) was prepared as described in Step 16a-b.

Step 16a: Preparation of cyclohexylsulfonamide

A solution of 18.5 mL (37.0 mmol) of 2M cyclohexylmagnesium chloride in ether was added dropwise to a solution of 3.0 mL (37.0 mmol) of freshly distilled sulfuryl chloride (obtained from Aldrich) in 100 mL of hexane cooled to -78 ° C. did. The mixture was warmed to 0 ° C. over 1 h and then carefully concentrated in vacuo. This mixture was redissolved in Et ₂ O (200 mL), washed with considerable ice-cold water (200 mL), dried (MgSO ₄ ) and carefully concentrated. This mixture was redissolved in 35 mL of THF and added dropwise to 500 mL of saturated NH ₃ in THF and left to stir overnight. The mixture was concentrated in vacuo to give a crude product as a yellow solid, the residue was filtered and concentrated through 50 g of silica gel using 70% EtOAc-hexane as eluent. The residue was recrystallized from CH ₂ Cl _{2 in} hexane with a minimum amount of 1-2 drops of MeOH to give 1.66 g (30%) of cyclohexylsulfonamide as a white solid. : ¹ H NMR (CDCl ₃ ) δ 1.11-1.37 (m, 3H), 1.43-1-1.56 (m, 2H), 1.67-1.76 (m, 1H), 1.86-1.96 (m, 2H), 2.18-2.28 (m , 2H), 2.91 (tt, J = 12, 3.5 Hz, 1H), 4.70 (bs, 2H); ¹³ C NMR (CDC1 ₃ ) δ 25.04, 25.04, 26.56, 62.74; MS m / e 162 (M−1 ) ^- .

Step 16b: Preparation of Compound 13 According to the method of Step 13b, 60 mg (0.087 mmol) of the product of Step 12e was added to 19.8 mg (0.122 mmol) CDI, cyclohexylsulfonamide 20 mg (0.122 mmol) and DBU 18 μL ( 0.122 mmol) to give 33.2 mg (46%) of foamy compound 13. ¹ H NMR (methanol-d ₄ ) δ 1.03 (s, 9H), 1.14-1.55 (m, 6H), 1.29 (s, 9H), 1.59-1.73 (m, 1H), 1.73-1.92 (m, 3H) , 2.04−2.23 (m, 3H), 2.30−2.49 (m, 1H), 2.63−2.69 (m, 1H), 3.41 (m, 1H), 3.94 (s, 3H), 4.04−4.13 (m, 1H) , 4.24−4.28 (m, 1H), 4.47−4.56 (m, 2H), 5.05−5.09 (m, 1H), 5.21−5.28 (m, 1H), 5.51 (m, 1H), 5.69−5.84 (m, 1H), 7.05 (dd, J = 9,2 Hz, 1H), 7.18 (s, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.47−7.55 (m, 3H), 7.99−8.07 (m , 3H) LC-MS (retention time: 1.72, method A), 832 (M ⁺ + H). MS m / z 832 (M + 1) ⁺ ; 830 (M−1) ⁻ .

Example 17
Compound 14, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 (lR, 2S vinyl Acca)- CONHS0 ₂ (neopentane), also known as {1- [2- [1- (2,2-dimethylpropane-1-sulfonylaminocarbonyl) -2-vinyl-cyclopropylcarbamoyl] -4- (7-methoxy-2) -(1R, 2S) P1 diastereomer (below) of -phenylquinolin-4-yloxy) pyrrolidine-1-carbonyl] -2,2-dimethylpropyl} carbamic acid tert-butyl ester as described in steps 17a-b Manufactured.

Step 17a: Production of neopentylsulfonamide

According to the method of step 16a, 49 mL (37 mmol) of 0.75M neopentylmagnesium chloride (Alfa) in ether was converted to 1.52 g (27%) of neopentylsulfonamide as a white solid. ¹ H NMR (CDC1 ₃ ) δ 1.17 (s, 9H), 3.12 (s, 2H), 4.74 (brs, 2H); ¹³ C NMR (CDC1 ₃ ) δ 29.46, 31.51, 67.38; MS m / e 150 (M −1) ^- .

Step 17b: Preparation of Compound 14 According to the method of Step 13b, 60 mg (0.087 mmol) of the product of Step 12e was replaced with 19.8 mg (0.122 mmol) CDI, neopentylsulfonamide 13.2 mg (0.096 mmol) and DBU 18 μL (0.122 mmol) to give 39.1 mg (55%) of a foamy compound. ¹ H NMR (methanol-d4, -1 / 2 rotamer) 8 1.04 (s, 9H), 1. 13,1.15 (two s (rotamers), 9H), 1.29 (s, 9H), 1.37−1.44 (m, 1H), 1.79, 1.88 (2 dd (rotamers), J = 8,5 Hz, 1H), 2.15−2.25 (m, 1H), 2.28−2.41 (m, 1H) , 2.61−2.72 (m, 1H), 3.14 (d, J = 13.9 Hz, 1H), 3.52 (d, J = 13.9 Hz, 1H), 3.94 (s, 3H), 4.06−4.15 (m, 1H ), 4.24−4.29 (m, 1H), 4.47−4.53 (m, 2H), 5.10 (d, J = 10.6 Hz, 1H), 5.25, 5.29 (two d (rotamers), J = 17 Hz , 1H), 5.53 (m, 1H), 5.70−5.86 (m, 1H), 6.54, 6.64 (2 d (rotamers), J = 9 Hz, 1H), 7.06 (d, J = 9 Hz , 1H), 7.19 (s, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.45−7.55 (m, 3H), 8.00−8.06 (m, 3H). LC-MS (retention time: 1.73, Method A), 820 (M ⁺ + H). MS m / z 820 (M + l) ⁺ ; 818 (M−1) ⁻ .

Example 18
Compound 15, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 (lR, 2S vinyl Acca)- CONHS0 ₂ (CH ₂ cyclobutane), also known as {1- [2- (1-cyclobutylmethanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) The (lR, 2S) P1 diastereomer of pyrrolidine-1-carbonyl] -2,2-dimethylpropyl} carbamic acid tert-butyl ester (below) was prepared as described in Step 18a-b.

Step 18a: Production of cyclobutyl carvinylsulfonamide

  A solution of 12.3 g (83 mmol) of cyclobutylcarbinyl bromide (Aldrich) and 13.7 g (91 mmol) of sodium iodide in 150 mL of acetone was refluxed overnight and then cooled to rt. The inorganic solid was collected by filtration, and acetone and cyclopropylcarbyl iodide (8.41 g, 46%) were distilled off at ambient temperature and 150 torr 80 ° C., respectively.

A solution of 4.0 g (21.98 mmol) of cyclobutylcarbyl iodide in 30 mL of anhydrous diethyl ether (Et ₂₀ ) cooled to −78 ° C. was added to a solution of 17 mL (21.98 mmol) of 1.3 M sec-butyllithium in cyclohexane. It was added through a tube and the solution was stirred for 5 min.

To this mixture was added through a tube to 3.0 g (21.98 mmol) of freshly distilled sulfuryl chloride in 110 mL of hexane cooled to −78 ° C., the mixture was warmed to rt over 1 h and then carefully concentrated in vacuo. The mixture was redissolved in Et ₂ 0, once significant ice - washed with cold water, dried (MgSO ₄₎ and concentrated carefully. This mixture was redissolved in 30 mL of THF, added dropwise to 500 mL of saturated NH ₃ in THF, and left to stir overnight. The mixture was concentrated in vacuo to give a crude product as a yellow solid that was recrystallized from CH ₂ Cl _{2 in} hexane with a minimum of 1-2 drops of MeOH to give 1.39 g of cyclobutyl carvinylsulfonamide as a white solid. (42%) was obtained. ¹ H NMR (CDC1 ₃ ) δ 1.81−2.03 (m, 4H), 2.142.28 (m, 2H), 2.81−2.92 (m, 1H), 3.22 (d, J = 7 Hz, 2H), 4.74 (brs , 2H); ¹³ C NMR (CDCl ₃ ) δ 19.10, 28.21, 30.64, 60.93; MS m / e 148 (M−1) ⁻ .

Step 18b: Compound 15
According to the method of step 13b, 100 mg (0.146 mmol) of the product of step 12e was combined with 33.1 mg (0.204 mmol) of CDI, 30 mg (0.204 mmol) of cyclobutylcarbvinylsulfonamide and DBU31 L (0.204 mmol). The reaction yielded 33 mg (28%) of foamy compound 15. ¹ H NMR (methanol-d ₄ , rotamer ˜2 / 3) δ 1.04, 1.05 (2 s (rotamers) 9H), 1.27, 1.30 (2 s (rotamers) 9H), 1.37−1.40 (m, 1H), 1.73−1.97 (m, 5H), 2.06−2.24 (m, 3H), 2.35−2.49 (m, 1H), 2.65−2.89 (m, 2H), 3.17−3.45 (m , 2H), 3.92, 3.93 (two s (rotamers) 3H), 4.04, 4.10 (two d (rotamers) J = 12 Hz, 1H), 4.23-4.28 (m, 1H), 4.49−4.57 (m, 2H), 5.03−5.08 (m, 1H), 5.20−5.27 (m, 1H), 5.53 (m, 1H), 5.77−5.88 (m, 1H), 6.54, 6.62 (two d (rotamers), J = 8 Hz, 1H), 7.06 (d, J = 9 Hz, 1H), 7.23 (s, 1H), 7.37 (s, 1H), 7.45-7.54 (m, 3H), . 8.03-8.09 (m, 3H) LC -MS ( retention time: 1.73, method ^{B), 818 (M + +} H)

Example 19
Compound 16, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 (lR, 2S vinyl Acca)- CONHS0 ₂ (CH ₂ cyclopropane), also known as {1- [2- (1-cyclopropylmethanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinoline-4- The (lR, 2S) P1 diastereomer of (yloxy) pyrrolidine-1-carbonyl] -2,2-dimethylpropyl} carbamic acid tert-butyl ester (below) was prepared as described in Steps 19a-b.

Step 19a: Cyclopropylcarbinyl sulfonamide

Cyclopropylcarbinyl sulfonamide was prepared from cyclopropylcarbinyl bromide (Aldrich) using the method of Step 18a (see also JACS 1981, p. 442-445). ¹ H NMR (CDCl ₃ ) δ 0.39-0.44 (m, 2H), 0.67-0.76 (m, 2H), 1.13-1.27 (m, 1H), 3.03 (d, J = 7.3 Hz, 2H), 4.74 (brs, 2H); ¹³ C NMR (CDC1 ₃ ) δ 4.33, 5.61, 59.93; MS m / e 134 (M−1) ⁻ .

Step 19b: Preparation of Compound 16 According to the method of Step 13b, 108 mg (0.159 mmol) of the product of Step 12e was replaced with 36 mg (0.222 mmol) CDI, 30 mg (0.222 mmol) cyclopropylcarbinyl sulfonamide and 33 μL DBU. Reaction with (0.222 mmol) gave 42 mg (33%) of foamy compound 16. ¹ H NMR (methanol-d ₄ , rotamer ˜2 / 3) δ 0.32−0.39 (m, 2H), 0.54−0.68 (m, 2H), 1.03 (s, 9H), 1.27, 1.29 (two s (rotamers), 9H), 1.08-1.41 (m, 1H), 1.55-1.86 (m, 2H), 2.10-2.25 (m, 1H), 2.35-2.51 (m, 1H), 2.62-2.80 ( m, 1H), 3.07−3.15 (m, 1H), 3.37−3.44 (m, 1H), 3.94, 3.94 (2 s (rotamers), 3H), 4.03−4.15 (m, 1H), 4.22 −4.28 (m, 1H), 4.51−4.60 (m, 2H), 4.99−5.08 (m, 1H), 5.18−5.28 (m, 1H), 5.55 (m, 1H), 5.77−5.94 (m, 1H) , 7.06 (d, J = 8.4 Hz, 1H), 7.25 (s, 1H), 7.38 (s, 1H), 7.46−7.56 (m, 3H), 8.03−8.12 (m, 3H). LC-MS (retention) Time: 1.68, Method D), 804 (M ⁺ + H). MS m / e 804 (M + 1) ⁺ ; 802 (m−1) ⁻ .

Example 20
Compound 17, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 (lR, 2S vinyl Acca)- CONHS02 (4-bromobenzenesulfonamide), also known as {1- [2- [1- (4-bromobenzenesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinoline) The (1R, 2S) P1 diastereomer of (-4-yloxy) pyrrolidine-1-carbonyl] -2,2-dimethylpropyl} carbamic acid tert-butyl ester (below) was prepared as follows.

A solution of the product of step 12e (0.035 g, 0.05 mmol) in THF (2 mL) was added to CDI (0.0165 g, 0.13 mmol) and the resulting solution was refluxed for 30 min and cooled to rt. To this solution was added 4-bromophenylsulfonamide (0.0482 g, 0.20 mmol) prepared by treating commercially available 4-bromosulfonyl chloride with saturated ammonia in THF, and then DBU (0.0194 mL, 0.13 mmol) was added. Added. The reaction 18 h stirring, diluted with EtOAc (lOOmL), pH 4.0 buffer (lOmL), washed with water (10 mL), brine (lOmL), dried (MgSO _4), column Isco LOG purification by (CH ₂ C1 ₂ 0% elution with 15% MeOH), to give a further purification is necessary product. The residue was purified using Analtech 20X40 cM 1000μ PTLC plate to give foamy compound 17 (0.0357 g, 79%): ¹ H NMR (methanol-d ₄ ) δ 1.03 (s, 9H), 1.26, 1.30 (2 s (rotamers), 9H), 1.43 (m, 1H), 1.74 (dd, J = 8,5 Hz, 1H), 2.02−2.21 (m, 1H), 2.32−2.47 (m, 1H), 2.58−2.66 (m, 1H), 3.92, 3.93 (two s (rotamers), 3H), 4.03−4.10 (m, 1H), 4.24 (m, 1H), 4.46− 4.58 (m, 2H), 4.87−4.91 (m, 1H), 5.13 (d, J = 17 Hz, 1H), 5.39−5.46 (m, 1H), 5.56−5.88 (m, 1H), 7.04 (dd, J = 9.2, 2.2 Hz, 1H), 7.20−7.18 (m, 1H), 7.35−7.37 (m, 1H), 7.44−7.58 (m, 5H), 7.68−7.79 (m, 2H), 8.00−8.10 ( . m, 3H) LC-MS ( retention time:. 1.77, method A) HRMS m / z (M + + H) C 44 H 51 SBrN 5 O 9: calc 904.2591, found 904.2580.

  This method can also be used as a general method for preparing aryl N-acylsulfonamides.

Example 21
Compound 18, {1- [2- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine-1-carbonyl]- The (1R, 2S) P1 diastereomer of 2,2-dimethyl-propyl} carbamic acid tetrahydrofuran-3 (S) -yl ester (below) was prepared as described in Steps 21a-b.

Step 21a: Production of chloroformate

  This method can be used for the production of chloroformates that are not commercially available. A solution of commercially available reagent (S) -3-hydroxytetrahydrofuran 5.96 g (67.6 mmol) and pyridine (5.8 mL; 72 mmol) in THF (150 mL) cooled to 0 ° C. was added toluene (48 mL, 92.6 mmol). ) Was added to a 1.93 M phosgene solution over 10 min under a stream of argon. The resulting solution was allowed to warm to rt over 2 h. The resulting solid was filtered and the mother liquor was carefully concentrated in vacuo at room temperature to give a theoretical amount. The resulting residue is dissolved in 100 mL of THF to prepare a 0.68M stock solution of 3 (S) -oxo-tetrahydrofuran chloroformate, which can be stored in a refrigerator until use. Similarly, other commercially available alcohols can be converted to a corresponding 0.68M stock solution of chloroformate.

Step 21b: Preparation of Compound 18 Product of Step 12e (1-{[l-2-tert-butoxycarbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenylquinoline-4- (Iloxy) pyrrolidine-2-carbonyl] amino} -2-vinylcyclopropanecarboxylic acid ethyl ester) solution of 3.5 grams (4.90 mmol) of (1R, 2S) P1 diastereomer was added to 170 mL (680 mmol) of 4N HCl in dioxane. ) For 2 h, then concentrated in vacuo to give 3.37 g (˜100%). ¹ H NMR (methanol-d ₄ ) δ 1.18 (s, 9H), 1.25 (t, J = 7.0 Hz, 1H), 1.44 (dd, J = 9.1, 5.1 Hz, 1H), 1.72 (dd, J = 8.1,5.5 Hz, 1H), 2.18−2.26 (m, 1H), 2.46−2.53 (m, 1H), 2.84 (dd, J = 14, 7 Hz, 1H), 4.06 (s, 3H), 4.09−4.27 (m, 4H), 4.53 (d, J = 12 Hz, 1H), 4.76−4.81 (m, 1H), 5.10 (dd, J = 10, 1.5 Hz, 1H), 5.27 (dd, J = 17.2, 1.5 Hz, 1H), 5.72−5.84 (m, 1H), 5.89 (m, 1H), 7.46 (dd, J = 9, 2,2 Hz, 1H), 7.64 (m, 2H), 7.68−7.79 (m, 3H), 8.08-8.16 (m, 2H), 8.42 (d, J = 9 Hz, 1H); ¹³ C NMR (methanol-d ₄ ) δ 14.62, 23.22, 26.70, 35.15, 35.89, 36.16, 40.90 , 55.30, 57.06, 60.44, 60.86, 62.46, 81.47, 100.56, 102.42, 116.03, 118.04, 121.92, 126.60, 130.14, 130.77, 133.24, 133.89, 135.18, 143.58, 158.19, 166.57, 167.87, 168.59, 87.52, 173. -MS (retention time: 1.41, method D), MS m / z 615 (M ⁺ +1). HRMS m / z (M + H) ⁺ C ₃₅ H ₄₃ N ₄ 0 ₆ : calculated value 615.3183, actual value 615.3185 .

To a slurry of 200 mg HCl (0.29 mmol) and Et ₃ N 220 μL (0.93 mmol) in 4 mL of THF, 0.93 mL (0.63 mmol) of a 0.68M solution of 3 (S) oxo-tetrahydrofuran chloroformate was added and the mixture was Stir overnight. The mixture is concentrated in vacuo and the residue is chromatographed on two 1000 μPTLC plates from Analtech (each eluted with 20 × 40 cm, 70% EtOAc-hexane) to give the desired P4 carbamate [tetrahydrofuran-3 (S) -yl. -O (C = O)] N-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) -S-proline] -P1 (lR, 115 mg (56%) of 2S vinyl Acca) -CO ₂ Et was obtained. ¹ H NMR (CDCl ₃ ) δ 1.02 (S, 9H), 1.22 (t, J = 7 Hz, 3H), 1.38−1.43 (m, 1H), 1.50−2.25 (m, 4H), 2.33−2.45 (m , 1H), 2.65 (dd, J = 13,7 Hz, 1H), 3.47−4.25 (m, 8H), 4.34−4.49 (m, 1H), 4.62 (m, 1H), 4.72 (m, 1H), 5.08 (d, J = 10 Hz, 1H), 5.25 (d, J = 17 Hz, 1H), 5.45 (m, 1H), 5.71−5.83 (m, 1H), 6.97−7.09 (m, 1H), 7.17 (s, 1H), 7.35 (s, 1H), 7.45-7.55 (m, 3H), 7.89-8.05 (m, 3H); ¹³ C NMR (CDC1 ₃ ) δ 14.64, 23.27, 26.92, 33.72, 35.01, 35.97 , 36.09, 36.22, 40.87, 54.99, 55.98, 60.32, 61.03, 62.380, 67.77, 73.90, 76.68, 77.99, 100.03, 107.52, 116.48, 118.01, 119.15, 124.23, 129.07, 128.96, 129.75, 130.52, 135.18, 141.29 , 158.08, 161.10, 161.80, 163.00 , 171.51, 172.84, 174.55 LC-MS. ( retention time: 1.35, method B), MS m / z 729.3 (M + + l).

To a solution of 80% THF-MeOH7.1 mL in 115 mg (0.164 mmol), was added a solution of H ₂ 02.8 mL of _{LiOH · H 2 0 40 mg (} 1.0 mmol). The mixture was stirred for 1 day, acidified with pH 7 (using 2N HCl) and concentrated in vacuo until only the aqueous layer remained. The solution was acidified with pH = 4 (using 2N HCl) and extracted repeatedly with EtOAc (3 × 50 mL). The combined EtOAc layers (150 mL) were dried (MgSO ₄ ), concentrated and 112 mg (˜100%) of the desired foamy carboxylic acid, [tetrahydrofuran-3 (S) -yl-O (C═ O)] N-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) -S-proline] -P1 (lR, 2S vinyl Acca)- CO ₂ H was obtained. ¹ H NMR (methanol-d ₄ ) δ 1.02, 1.03 (2 s (rotamers), 9H), 1.42-1.45 (m, 1H), 1.58-1.65 (m, 1H), 1.67-1.70 (m , 1H), 1.82-1-1.90 (m, 1H), 2.15−2.21 (m, 1H), 2.46−2.51 (m, 1H), 2.70−2.74 (m, 1H), 3.59−3.90 (m, 4H), 3.95 (s, 3H), 4.05 (dd, J = 12, 3 Hz, 1H), 4.23−4.26 (m, 1H), 4.52 (d, J = 12 Hz, 1H), 4.62−4.77 (m, 2H), 5.07−5.10 (m, 1H), 5.23−5.27 (m, 1H), 5.57 (m, 1H), 5.80−5.88 (m, 1H), 7.09−7.15 (m, 1H), 7.27 (m, 1H), 7.40 (m, 1H), 7.49-7.56 (m, 3H), 8.04-8.09 (m, 3H); LC-MS (retention time: 1.48, method D): MS m / e 701 (M ⁺ +1).

[Tetrahydrofuran-3 (S) -yl-O (C = O)] N-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxy-quinoline) in THF (5.8 mL) -4-oxo) -S-proline] -P1 (lR, 2S vinyl Acca) -CO ₂ H (0.156 g, 0.223 mmol) and CDI (0.0471 g, 0.291 mmol) were refluxed for 40 min and left to stand. And cooled to rt. Cyclopropylsulfonamide (0.0533 g, 0.447 mmol) was added in one portion followed by a solution of DBU (0.0422 mg, 0.291 mmol). The reaction 18 h stirring, diluted with EtOAc (lOOmL), washed with pH 4.0 buffer (3 × 30 mL), water (20 mL), brine (20 mL), dried (MgSO _4), Biotage 40 M column (Eluted with CH ₂ Cl ₂ 0% to 4% MeOH) to give the desired product [tetrahydrofuran-3 (S) -yl-O (C═O)] N—P 3 (Lt-BuGly) — P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline] -P1 (lR, 2S vinyl Acca) -CONHS0 ₂ -cyclopropane, also known as compound 18, {l- [2- (1-Cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropyl carbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidin-1-carbonyl] -2,2-dimethyl- (1R, 2S) P1 diastereomer of propyl} carbamic acid tetrahydrofuran-3 (S) -yl ester (0.117 g, 65%) Was obtained as a foam. ¹ H NMR (methanol-d ₄ ) δ 1.02-1.07 (m, 11H), 1.22-1.28 (m, 2H), 1.42-1.45 (m, 1H), 1.57-1.64 (m, 1H), 1.80-1.92 ( m, 2H), 2.19−2.27 (m, 1H), 2.31−2.41 (m, 1H), 2.68 (dd, J = 14,7 Hz, 1H), 2.90−2.96 (m, 1H), 3.61−3.81 ( m, 4H), 3.95 (s, 3H), 4.07−4.11 (m, 1H), 4.25−4.29 (m, 1H), 4.49−4.60 (m, 2H), 4.72−4.76 (m, 1H), 5.10− 5.13 (m, 1H), 5.27−5.33 (m, 1H), 5.59 (m, 1H), 5.72−5.80 (m, 1H), 7.10−7.14 (m, 1H), 7.28 (m, 1H), 7.41 ( m, 1H), 7.49-7.58 (m, 3H), 8.05-8.08 (m, 3H); LC-MS (retention time: 1.37, method D), MS m / z 804 (M ⁺ +1).

  This method of Example 21 can be generally used to prepare the carbamate N-acylsulfonamides of the present invention.

Example 22
Compound 19, [tert-butyl-NH (C = O)] NH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline ] -P1 (lR, 2S vinyl Acca) -BOCNH-2-cyclopropane, also known as 1- [2- (3-tert-butylureido) -3,3-dimethylbutyryl] -4- (7-methoxy 2- (phenylquinolin-4-yloxy) pyrrolidine-2-carboxylic acid (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropyl) amide (1R, 2S) P 1 diastereomer (below) was prepared in steps 22a-c And was prepared as described in

Step 22a: [tert-Butyl-NH (C = O)]] NH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S- Proline] -P1 (lR, 2S vinyl Acca) -C0 ₂ Et
THF 3 mL of _{NH 2 -P3 (L-t-} BuGly) -P2 [(4R) - (2- phenyl-7-methoxyquinoline-4-oxo) -S- proline] -P1 (lR, 2S vinyl Acca) - Commercially available tert-butyl isocyanate 57 μL (0.50 mmol) was added to a slurry of C 0 ₂ Et · dihydrochloride 175 mg (0.245 mmol) and Et ₃ N139 μL (1.0 mmol). The mixture was stirred overnight, diluted with 20 mL pH 4.0 buffer and extracted with 4 x 50 mL portions of EtOAc. The combined organic layers were concentrated in vacuo and the residue was chromatographed on a biotage 25 M column (eluting with 15% to 100% EtOAc / hexanes) to give 152 mg (86%) of the title compound. ¹ H NMR (CDCl ₃ ) δ 1.03 (s, 9H), 1.17 (s, 9H), 1.34-1.45 (m, 1H), 1.61-1.74 (m, 1H), 2.15-2.24 (m, 1H), 2.32 −2.51 (m, 1H), 2.61−2.75 (m, 1H), 3.92 (m, 3H), 4.01−4.17 (m, 3H), 4.32 (m, 1H), 4.51−4.60 (m, 2H), 5.07 (d, J = 11 Hz, 1H), 5.24 (d, J = 17 Hz, 1H), 5.53 (m, 1H), 5.69−5.81 (m, 1H), 7.00−7.11 (m, 1H), 7.21 ( m, 1H), 7.36 (m, 1H), 7.44-7.58 (m, 3H), 8.02-8.13 (m, 3H); LC-MS (retention time: 2.36, method A), MS m / z 714 (M ⁺ +1).

Step 22b: [tert-Butyl-NH (C = O)] HN-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline ] -P1 (lR, 2S vinyl Acca) -CO ₂ H production
To a solution of 152 mg (0.21 mmol) of the product of step 22a in 9.4 mL of 80% THF-MeOH was added a solution of LiOH.H ₂ 052 mg (1.3 mmol) in 03.9 mL of H ₂ . The mixture was stirred for 1 day, acidified to pH 7 (using 2N HCl) and concentrated in vacuo until only the aqueous layer remained. The solution was acidified to pH = 4 (using 2N HCl) and extracted repeatedly with EtOAc (3 × 50 mL). The combined EtOAc layer (150 mL) was dried (MgSO ₄ ) and concentrated to give 122 mg (85%) of the foamy title compound. ¹ H NMR (methanol-d ₄ ) δ 1.01 (s, 9H), 1.30 (s, 9H), 1.38−1.42 (m, 1H), 1.81−2.28 (m, 2H), 2.22−2.64 (m, 2H) , 3.94 (s, 3H), 4.12 (dd, J = 12, 4 Hz, 1H), 4.34−4.41 (m, 1H), 4.51 (d, J = lO Hz, 1H), 4.69 (d, J = 11 Hz, 1H), 4.79 (m, 1H), 5.08 (d, J = 12 Hz, 1H), 5.21 (d, J = 17 Hz, 1H), 5.33 (m, 1H), 5.57−5.72 (m, 1H ), 6.95 (s, 1H), 7.05 (dd, J = 9, 2,2.6 Hz, 1H), 7.40−7.53 (m, 4H), 8.01−8.03 (m, 2H), 8.09 (d, J = 9.2 Hz, 1H). LC-MS (retention time: 1. 37, method B) m / z 686 (M ⁺ +1).

Step 22c: Preparation of Compound 19
A solution of the product of step 22b (0.120 g, 0.0.175 mmol), CDI (0.0368 g, 0.227 mmol) in THF (5.8 mL) was refluxed for 40 min and allowed to cool to rt. Cyclopropylsulfonamide (0.0416 g, 0.349 mmol) was added in one portion followed by a solution of DBU (0.0345 mg, 0.227 mmol). The reaction 18 h stirring, diluted with EtOAc (lOOmL), washed with pH 4.0 buffer (3 × 30 mL), water (20 mL), brine (20 mL), dried (MgSO _4), Biotage 40 M column Purification (eluting with 0% to 4% MeOH in CH ₂ Cl ₂ ) afforded foamy compound 19 (0.0872 g, 63%). ¹ H NMR (methanol-d ₄ ) δ 1.04 (s, 9H), 1.17 (s, 9H), 1.15-1.31 (m, 4H), 1.40 (dd, J = 9.5, 5.2 Hz, 1H), 1.86 (dd , J = 8,5 Hz, 1H), 2.16−2.22 (m, 1H), 2.30−2.37 (m, 1H), 2,65 (dd, J = 14, 7, 1H), 2.90−2.95 (m, 1H), 3.94 (s, 3H), 4.11 (dd, J = 11.7, 3.7 Hz, 1H), 4.35 (s, 1H), 4.50 (dd, J = 10.4, 7 Hz, 1H), 4.57 (d, J = 12 Hz, 1H), 5.09 (dd, J = 10,2 Hz, 1H), 5.26 (dd, J = 17,2 Hz, 1H), 5.56 (m, 1H), 5.70−5.77 (m, 1H) , 7.07 (dd, J = 9.2, 2 Hz, 1H), 7.25 (s, 1H), 7.38 (d, J = 2 Hz, 1H), 7.48−7.55 (m, 3H), 8.04−8.06 (m, 2H ), 8.10 (d, J = 9.2 Hz, 1H). LC-MS (retention time: 1.51, method D) MS m / e 789 (M ⁺ +1).

Example 23
Compound 20: 1- {2- [3-cyclopropylmethyl-3- (3,3,3-trifluoropropyl) ureido] -3,3-dimethylbutyryl} -4- (7-methoxy-2-phenyl) The (1R, 2S) P1 diastereomer of quinolin-4-yloxy) -pyrrolidine-2-carboxylic acid (1-cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) amide (below) is described in Steps 23a-b. It manufactured as follows.

ＣＨ₂Ｃl₂(100 mL)中３,３,３−トリフルオロ酢酸(9.7 mL, 110 mmoles)およびＮ−ヒドロキシスクシンイミド(13.92 g, 1.1当量)の溶液を、０℃にてＥＤＡＣ(21.08 g, 1当量)で処理した。混合物を放置して室温まで温めた。一夜攪拌後、溶媒を蒸発させ、残渣をＥtＯＡcおよび水に分配した。有機相を食塩水で洗滌し、ＭgＳＯ₄で乾燥させ、蒸発させ、粗活性エステルを得、これをさらに精製することなく用いた(22.78 g, 92%)。¹Ｈ ＮＭＲ(CDCl₃) δ 2.86 (s, 4H), 3.51 (m, 2H). Step 23a: Preparation of 3,3,3-trifluoropropylamine hydrochloride in cyclopropylmethyl-

A solution of 3,3,3-trifluoroacetic acid (9.7 mL, 110 mmoles) and N-hydroxysuccinimide (13.92 g, 1.1 eq) in CH ₂ Cl ₂ (100 mL) was added EDAC (21.08 g, 1 equivalent). The mixture was allowed to warm to room temperature. After stirring overnight, the solvent was evaporated and the residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO ₄ and evaporated to give the crude active ester which was used without further purification (22.78 g, 92%). ¹ H NMR (CDCl ₃ ) δ 2.86 (s, 4H), 3.51 (m, 2H).

A stirred solution of 3,3,3-trifluoroacetic acid N-hydroxysuccinimide active ester (12.98 g, 57.65 mmoles) in CH ₂ Cl ₂ (80 mL) at 0 ° C. was added with cyclopropylmethylamine (5.0 mL, 1 eq). Processed. The mixture was stirred at room temperature for 14 hours and evaporated. The residue was partitioned between EtOAc and water and the organic phase was washed with water, brine, dried over MgSO ₄ and evaporated to give the crude amide. This was dried under high vacuum for several hours and then under a nitrogen stream at 0 ° C. Carefully treated with a 1M solution of borohydride in tetrahydrofuran (173 mL, 3 eq, 173 mmol). The mixture was heated to reflux for 14 hours and then cooled again to 0 ° C. MeOH (50 mL) was added very carefully to avoid excessive foaming and the mixture was heated to reflux for 5 hours. After cooling again to 0 ° C., a solution of t-butyl pyrocarbonate (17.62 g, 1.4 eq) in CH ₂ Cl ₂ (25 mL) was added. The resulting mixture was stirred at room temperature overnight and then evaporated. The residue was partitioned between EtOAc and water, the organic layer was washed with water, brine, dried (MgSO _4), and evaporated to give the crude Boc- protected amine. This was dissolved in CH ₂ Cl ₂ (25 mL) and treated with 4M HCl in dioxane (36 mL, 2.5 eq, 144 mmol) and the mixture was stirred at room temperature overnight and then evaporated. The resulting white solid was triturated with ether and the product was collected by filtration, washed with ether and dried in vacuo (10.10 g, 86%). ¹ H NMR δ (D ₂ 0) 0.36 (m, 2H), 0.67 (m, 2H), 1.07 (m, 1H), 2.72 (m, 2H), 2.99 (m, 2H), 3.89 (m, 2H) .

This process step can be used for the preparation of the tripeptide P4 N-terminal dialkylurea from the dialkylamine hydrochloride and the tripeptide N-terminal isocyanate and then for the preparation of the compounds of the invention. Tripeptide isocyanate is produced in the same manner as described in SynLett. Feb. 1995; (2); 142-144, using a tertiary hindered base such as DIPEA or an amine component such as Et ₃ N and phosgene. can do.

Step 23b: Compound 20 CH ₂ Cl ₂ 8 mL of this HCl salt 110 mg cooled to manufacture 0 ℃ of (0.0.16 mmol) and the slurry of DIPEA400 μL (2.30 mmol), commercially available triphosgene 62 mg (0.21 mmol) Was added. The mixture was stirred for 3 h, 73.4 mg (0.36 mmol) of cyclopropylmethyl-3,3,3-trifluoropropylamine hydrochloride was added and the reaction vessel was left to warm at rt overnight. The mixture was diluted with 20 mL of pH 4.0 buffer and extracted with 4 × 50 EtOAc. The combined organic layers were washed once with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ), concentrated in vacuo, and the residue was chromatographed on a biotage 40+ M column (eluting with 30% to 50% EtOAc / hexane). And 68 mg (48%) of the desired P4 dialkylurea [N, N-cyclopropylmethyl-3,3,3-trifluoropropyl]-(C = O)] HN-P3 (Lt-BuGly ) -P2 [(4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) -S-proline] -P1 (1R, 2S vinyl Acca) -C0 ₂ Et was obtained: ¹ H NMR (CDCl ₃ / Methanol-d ₄ ) δ 0.19−0.22 (m, 2H), 0.49−0.53 (m, 2H), 0.77−0.92 (m, 1H), 1.05 (s, 9H), 1.24 (t, J = 7 Hz , 3H), 1.42 (dd, J = 9,5 Hz, 1H), 1.72 (dd, J = 8, 5 Hz, 1H), 2.17−2.22 (m, 1H), 2.27−2.35 (m, 2H), 2.40−2.45 (m, 1H), 2.68−2.73 (m, 1H), 3.01 (dd, J = 15,6 Hz, 1H), 3.08 (dd, J = 15,6 Hz, 1H), 3.30−3.46 ( m, 2H), 3.95 (s, 3H), 4.05−4.20 (m, 3H), 4.46 −4.51 (m, 2H), 4.62−4.66 (m, 1H), 5.09 (d, J = 10 Hz, 1H), 5.26 (d, J = 17 Hz, 1H), 5.57 (m, 1H), 5.74− 5.81 (m, 1H), 7.09 (dd, J = 9, 2 Hz, 1H), 7.26 (s, 1H), 7.39 (d, J = 2 Hz, 1H), 7.51-7.56 (m, 3H), 8.04 -8.06 (m, 3H); LC-MS (retention time: 1.79, method B) MS m / z 808 (M ⁺ +1).

P4 dialkylurea [N, N-cyclopropylmethyl-3,3,3-trifluoropropyl]-(C = O)] HN-P3 (Lt-BuGly)-in a solution of 4 mL of THF and 2.5 mL of MeOH To a solution of P2 [(4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) -S-proline] -P1 (lR, 2S vinyl Acca) -C0 ₂ Et 65 mg (0.081 mmol), solution of ₂ 0 2 mL of LiOH 12 mg (0.48 mmol) was added. The mixture was stirred overnight and a further 6 mg (0.24 mmol) portions of LiOH was added and the mixture was stirred for 12 h. The mixture was acidified to pH 5 (using 2N HCl) and concentrated in vacuo until only the aqueous layer remained. The solution was extracted repeatedly with EtOAc (5X 15 mL). The combined EtOAc layers (75 mL) were dried (MgSO ₄ ), concentrated and 58 mg (92%) of the desired carboxylic acid, [N, N-cyclopropylmethyl-3,3,3-trifluoropropyl. ]-(C = O)] HN P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) -S-proline] -P1 (lR, 2S Vinyl Acca) -CO ₂ H was obtained as a foam: ¹ H NMR (CDC1 ₃ -methanol-d ₄ ) δ 0.25-0.28 (m, 2H), 0.560.62 (m, 2H), 0.85-0.98 ( m, 1H), 1.09 (s, 9H), 1.46−1.49 (m, 1H), 1.77 (dd, J = 8,5 Hz, 1H), 2.18−2.23 (m, 1H), 2.33−2.43 (m, 2H), 2.56−2.61 (m, 1H), 2.69 (dd, J = 14,8 Hz, 1H), 3.08 (dd, J = 15, 6 Hz, 1H), 3.16 (dd, J = 15, 6Hz, 1H), 3.43−3.53 (m, 2H), 3.98 (s, 3H), 4.13 (dd, J = 12, 4 Hz, H), 4.50−4.53 (m, 2H), 4.69 (t, J = 8 Hz , 1H), 5.11−5.13 (m, 1H), 5.28−5.32 (m, 1H), 5.54 (m, 1H), 5.82−5.90 (m, 1H), 7.11 (dd, J = 9, 2 Hz, 1H ), 7.19 (s, 1H), 7.43 (d, J = 2 Hz, 1H), 7.5 1−7.58 (m, 3H), 7.99−8.05 (m, 2H), 8.08 (d, J = 9 Hz, 1H); LC-MS (retention time: 1.63, method A), MS m / z 780 (M ⁺ +1).

[N, N-cyclopropylmethyl-3,3,3-trifluoropropyl]-(C = O)] HN-P3 (Lt-BuGly) -P2 [(4R)-( 2-phenyl-7-methoxy - quinoline-4-oxo) -S- proline] -P1 (lR, 2S vinyl _{Acca) -C0 2 H (58 mg} , 0.74 mmol) and CDI (17 mg, solution of 0.104 mmol) Was refluxed for 60 min and allowed to cool to rt. Cyclopropylsulfonamide (13 mg, 0.104 mmol) was added in one portion followed by a solution of DBU (16 CL, 0.104 mmol). The reaction was stirred for 72 h and diluted with EtOAc (lOOmL). The solution was washed with pH 4.0 buffer (2 × 20 mL) and dried (MgSO4), concentrated, and chromatographed on Analtech Inc. 1000p PTLC plate (20X40 cm, eluted with CH ₂ C1 ₂ in 2% MeOH), foam compound 20 18 mg (27%) obtained: ¹ H NMR (CDC1 ₃ - methanol _{-d 4) δ 0.22-0.27 (m,} 2H), 0.50-0.56 (m, 2H), 0.86-0.94 (m, 1H), 1.00−1.11 (m, 2H), 1.09 (s, 9H), 1.18−1.25 (m, 2H), 1.46−1.48 (m, 1H), 1.90 (dd, J = 8, 5 Hz, 1H) , 2.18−2.24 (m, 1H), 2.30−2.46 (m, 3H), 2.70 (dd, J = 14,8 Hz, 1H), 2.80 (m, 1H), 3.07 (dd, J = 15, 7 Hz , 1H), 3.13 (dd, J = 15, 7 Hz, 1H), 3.43−3.49 (m, 2H), 3.98 (s, 3H), 4.16 (dd, J = 12, 3 Hz, 1H), 4.50− 4.54 (m, 2H), 4.57−4.61 (m, 1H), 5.12 (d, J = 12 Hz, 1H), 5.30 (d, J = 17 Hz, 1H), 5.63 (m, 1H), 5.75 (d , J = 9 Hz, 1H), 5.83−5.90 (m, 1H), 7.13 (dd, J = 9,2 Hz, 1H), 7.31 (s, 1H), 7.43 (d, J = 2 Hz, 1H) , 7.52-7.59 (m, 3H), 8.08-8.10 (m, 3H); LC-MS. ( retention time: 1.65, method A), MS m / z 883 (M + +1) MS m ^{e 883.2 (M + 1) +} , 881 (M-1) -.

Example 24
Compound 21, N-Boc-P3- (L-Val) -P2 [(4R)-(2-phenyl-7-methoxy-quinoline-4-oxo) -proline)]-P1- (1-aminocyclopropane- 1-) CONH-2-cyclopropane was prepared as described in steps 24a-d below.

In step 24a, the product, P2 HN-[(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline methyl ester dihydrochloride] is converted to N-Boc-P2 [(4R) -(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline (N-Boc (4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline, 4- (7 -Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester).

Specifically, N-Boc (4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline, 4- (7-methoxy-2-phenyl) in 500 mL of MeOH cooled to −78 ° C. -Quinolin-4-yloxy) -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 10 g (21.5 mmol) was bubbled with HCl gas for 10 min. The mixture was warmed to rt, stirred overnight and concentrated in vacuo. The residue was repeatedly codistilled with toluene and dioxane to give 9.71 g (100%) of the off-white title compound. ¹ H NMR (DMSO-d ₆ ) δ 2.56−2.66 (m, 1H), 2.73−2.80 (m, 1H), 3.67−3.86 (m, 2H), 3.79 (s, 3H), 3.97 (s, 3H) , 4.76−4.82 (m, 1H), 5.95 (m, 1H), 7.42 (dd, J = 9, 2 Hz, 1H), 7.65−7.72 (m, 4H), 8.23−8.27 (m, 2H), 8.51 (d, J = 9.2 Hz, 1H), 9.68 (bs, 1H), 11.4 (bs, 1H); LC-MS (retention time: 0.94, method D), MS m / e 379 (M ⁺ +1).

In step 24b, the product, 1- (2-tert-butoxy-carbonylamino-3-methylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2-carboxylic acid (below) also, alias, P3 N-BOC (L- Val) -P2 [(4R) - (2- phenyl-7-methoxyquinoline-4-oxo) proline)] - was prepared C0 ₂ H.

Specifically, [HN- (4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline) methyl ester / bishydrochloride] 1.95 g (4.32 mmol) in DMF (20 mL), HATU1.81 g (4.76 mmol) was added to a suspension of N-Boc-1-valine 1.22 g (5.62 mmol) and NMM 1.89 mL (17.28 mmol) at 0 ° C. Warmed reaction mixture overnight until left slowly rt, and stirred for 2 days, diluted with EtOAc (100 mL), pH 4.0 buffer (2 × 50 mL), saturated aqueous NaHC0 ₃ (50 mL), brine (50 mL) Wash with and dry (MgSO ₄ ), purify on a Biotage 40 M column (eluting with 15% to 100% EtOAc in hexanes) and obtain 2.39 g (96%) of foamy 1- (2-tert-butoxycarbonyl). -Amino-3-methyl-butyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2-carboxylic acid methyl ester (also known as P3 N-BOC (L-Val) -P2 [ (4R) - (2-phenyl-7-methoxyquinoline-4-oxo) proline)] - CO ₂ Me) was obtained. ¹ H NMR (CDC1 ₃ ) δ 0.98 (d, J = 7 Hz, 3H), 1.05 (d, J = 7 Hz, 3H), 1.34 (s, 9H), 2.00−2.11 (m, 1H), 2.31− 2.40 (m, 1H), 2.79 (dd,
J = 14,8 Hz, 1H), 3.77 (s, 3H), 3.96 (s, 3H), 4.04−4.14 (m, 1H), 4.21−4.26 (m, 1H), 4.49 (d, J = 12 Hz , 1H), 4.75 (t, J = 8 Hz, 1H), 5.13 (d, J = 8 Hz, 1H), 5.35 (m, 1H), 6.96 (s, 1H), 7.09 (dd, J = 9, 2 Hz, 1H), 7.41-7.55 (m, 4H), 7.99-8.04 (m, 3H); LC-MS (retention time: 1.40, method A), MS m / e 578 (M ⁺ +1).

1- (2-tert-butoxycarbonylamino-3-methylbutyryl) -4- (7-methoxy-2-phenylquinoline- in THF (223 mL), CH ₃ 0H (30 mL) and H ₂ 0 (119 mL) A solution of 4-yloxy) -pyrrolidine-2-carboxylic acid methyl ester (2.865 g, 4.96 mmol) was added to LiOH (952 mg, 39.7 mmol). The reaction mixture is stirred for 1 day, acidified to neutral pH, concentrated in vacuo until only the aqueous layer remains, the resulting aqueous residue is acidified by adding 1.0 N aqueous HCl to pH 4.0, and solid NaCl. Saturated with This aqueous mixture was repeatedly extracted with EtOAc (5 × 200 mL), the combined organic solvents were dried (Mg ₂ SO ₄ ), filtered, concentrated in vacuo and the foamy title compound 2.77 g (99%) Got. ¹ H NMR (CDC1 ₃ ) δ 0.97 (d, J = 7 Hz, 3H), 1.03 (d, J = 7 Hz, 3H), 1.19 (s, 9H), 1.94−2.06 (m, 1H), 2.37− 2.47 (m, 1H), 2.83 (dd,
J = 14,8 Hz, 1H), 3.96 (s, 3H), 4.02−4.09 (m, 2H), 4.63−4.69 (m, 2H), 5.58 (m, 1H), 6.74 (d, J = 8 hz , 1H), 7.15 (dd, J = 9 Hz, 1H), 7.29 (s, 1H), 7.40 (d, J = 2 Hz, 1H), 7.51−7.61 ((m, 3H), 8.03−8.06 (2H ), 8.15 (d, J = 9 Hz, 1H); LC-MS (retention time: 1.36, method A), MS m / z 564 (M ⁺ +1).

In step 24c, the product 1-{[1- (2-tert-butoxycarbonylamino-3-methylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yl-oxy) pyrrolidine-2-carbonyl Amino} cyclopropanecarboxylic acid (below), also known as BOC P3- (L-Val) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)]-P1 -(1-Aminocyclopropanecarboxylic acid) was prepared.

Specifically, HCl gas was bubbled into a solution of 3.0 g (14.9 mmol) of commercially available 1-tert-butoxycarbonylaminocyclopropane-carboxylic acid in 60 mL of MeOH cooled to −78 ° C. for 10 min. The mixture was warmed to rt, stirred overnight and concentrated in vacuo to give 2.26 g (100%) of 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride as a white solid. ¹ H NMR (methanol-d ₄ ) δ 1.36-1.39 (m, 2H), 1.55-1.58 (m, 2H), 3.80 (s, 3H).

Then, the product 400 mg of _{50% CH 2 C1 2 / THF} (15mL) medium step 24b (0.71 mmol), 1- amino-cyclopropanecarboxylic acid methyl ester dihydrochloride 155 mg (0.92 mmol), and NMM0.40 To a suspension of mL (3.55 mmol), PyBrop 0.43 g (0.92 mmol) was added at 0 ° C. The reaction mixture was slowly warmed to rt and left overnight. Dilute with EtOAc (500 mL), wash with pH 4.0 buffer (2 × 50 mL), saturated aqueous NaHCO ₃ (50 mL), brine (50 mL), dry (MgSO ₄ ), Biotage 40 M column (0% To 1% MeOH / EtOAc and purified by 1-{[1- (2-tert-butoxycarbonylamino-3-methyl-butyryl) -4- (7-methoxy-2-phenyl-quinoline-4- Yl-oxy) pyrrolidine-2-carbonyl] amino} -cyclopropanecarboxylic acid methyl ester (also known as BOC P3- (L-Val) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) ) -S-proline)]-P1- (1-aminocyclo-propanecarboxylic acid methyl ester) 308 mg (66%) was obtained as a foam. ¹ H NMR (methanol-d ₄ ) δ 0.95 (d, J = 7 Hz, 3H), 0.98 (d, J = 7 Hz, 3H), 1.24 (s, 9H), 1.39−1.56 (m, 4H), 1.89−2.05 (m, 1H), 2.41−2.48 (m, 1H), 2.70 (dd, J = 14,8 Hz, 1H), 3.66 (s, 3H), 3.91 (s, 3H), 4.02−4.05 ( m, 2H), 4.52−4.63 (m, 2H), 5.47 (m, 1H), 7.04 (dd, J = 9,2 Hz, 1H), 7.18 (m, 1H), 7.34 (d, J = 2 Hz , 1H), 7.45-7.55 (m, 3H), 8.03-8.06 (m, 3H); ¹³ C NMR (methanol-d ₄ ) δ 17.36, 18.03, 18.98, 19.64, 28.54, 31.66, 34.36, 35.89, 52.92, 54.38, 55.97, 59.68, 60.42, 77.96, 80.41, 99.96, 107.55, 116.43, 119.16, 124.27, 128.96, 129.72, 130.47, 141.31, 152.22, 157.86, 161.22, 161.85, 163.03, 173.91, 174.28, 174.83; LC- ( Retention time: 1. 39, method A) MS m / e 661 (M ⁺ +1).

Next, 1-{[1- (2-tert-butoxycarbonylamino-3-methylbutyryl) -4- (7-) in THF (21 mL), CH ₃ 0H (3 mL) and H ₂ 0 (11 mL). To a solution of methoxy-2-phenylquinolin-4-yl-oxy) pyrrolidine-2-carbonyl] amino} cyclopropanecarboxylic acid methyl ester (308 mg, 0.47 mmol) was added LiOH (56 mg, 2.33 mmol). The reaction mixture is stirred for 1 day, acidified to neutral pH, concentrated in vacuo until only the aqueous layer remains, the resulting aqueous residue is acidified by adding 1.0 N aqueous HCl to pH 4.0, and solid NaCl. Saturated with This aqueous mixture was repeatedly extracted with EtOAc (3 × 50 mL) and the combined organic solvents were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 292 mg (95%) of the foamy title compound. It was. ¹ H NMR (methanol-d ₄ ) δ 0.96 (d, J = 7 Hz, 3H), 0.99 (d, J = 7 Hz, 3H), 1.17 (s, 9H), 1.09−1.47 (m, 4H), 1.51-1.60 (m, 1H), 1.90−2.00 (m, 1H), 2.50−2.59 (m, 1H), 2.80 (dd, J = 14,8 Hz, 1H), 3.99 (s, 3H), 4.02− 4.12 (m, 1H), 4.62 (m, 2H), 5.69 (m, 1H), 7.24 (dd, J = 9, 2.4 Hz, 1H), 7.45 (s, 1H), 7.60−7.66 (m, 3H), 8.02-8.08 (m, 2H), 8.23 (d, J = 9 Hz, 1H). LC-MS (retention time: 1.50, method D) MS m / z 647 (M ⁺ +1).

In step 24d, compound 21 is prepared by adding CDI (81.2 mg, 0.50 mmol) to a solution of the product of step 24c (0.270 g, 0.42 mmol) in THF (3 mL) and then refluxed for 60 min. It was. The solution was allowed to cool to rt. Cyclopropylsulfonamide (0.0607 g, 0.50 mmol) was then added in one portion and a precisely measured solution of DBU (0.075 mL, 0.50 mmol) was added. The reaction was stirred for 18 h, diluted with EtOAc (200 mL), washed with pH 4.0 buffer (3 × 30 mL), water (2 × 30 mL), brine (30 mL), dried (MgSO ₄ ), 20 × 40 cM 1000p Analtech PTLC plate (CH ₂ eluting with C1 ₂ in 2% MeOH) as eluant to afford a foamy compound 21 (o.113g, 40%): LC / MS rt-min (MH +): 1.49 ( 750) (method A) ¹ H NMR:. (methanol _{-d 4, 30OMHz) δ 0.88-1.18 (} m, 10H), 1.23 (s, 9H), 1.37-1.79 (m, 4H), 2.00-2.09 (m , 1H), 2.43−2.53 (m, 1H), 2.63−2.76 (m, 1H), 2.76−2.89 (m, 1H), 3.94 (s, 3H), 4.02−4.11 (m, 2H), 4.54−4.62 (m, 2H), 5.57 (m, 1H), 7.09 (dd, J = 9,2 Hz, 1H), 7.25 (s, 1H), 7.38 (d, J = 2 Hz, 1H), 7.49-7.57 ( m, 3H), 8.03-8.11 (m, 3H).

Example 25
Compound 22, 1- [2- (1-cyclopropanesulfonylaminocarbonylcyclobutylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1-carbonyl] -2,2- Dimethylpropyl} carbamic acid tert-butyl ester (below), also known as BOC P3- (1-tBuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline)] -P1- (1- aminocyclobutane -1-) CONHS0 ₂ - cyclopropane was prepared as described in step 25a-d.

In step 25a, the product, 1- (2-tert-butoxy-carbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carboxylic acid (below), also known, P3 N-BOC (L- t-BuGly) -P2 [(4R) - (2- phenyl-7-methoxyquinoline-4-oxo) -S- proline)] - CO ₂ H, a Manufactured using two sequential steps.

Specifically, [HN- (4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline) methyl ester / bishydrochloride] 3.90 g (8.60 mmol) in DMF (20 mL), HATU 3.62 g (9.52 mmol) was added at 0 ° C. to a suspension of N-Boc-1-tert-leucine (1-tBuGly) 2.65 g (11.47 mmmol) and NMM 3.48 g (34.40 mmol). . The reaction mixture was slowly warmed to rt, left overnight, stirred for 4 days, diluted with EtOAc (200 mL), washed with pH 4.0 buffer (3 × 40 mL), saturated aqueous NaHCO ₃ (40 mL) and dried ( MgSO ₄ ), Biotage 40 M column (eluting with 15% to 70% EtOAc / hexane). Foamed 1- (2-tert-butoxycarbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2-carboxylic acid methyl ester, also known as , P3 N-BOC (1- tBuGly) -P2 [(4R) - (2- phenyl-7-methoxyquinoline-4-oxo) -S- proline)] - CO ₂ Me, give 4.16 g (81%) It was. ¹ H NMR (CDC1 ₃ ) δ 1.07 (s, 9H), 1.37 (s, 9H), 2.29-2.39 (m, 1H), 2.78 (dd, J = 14,8 Hz, 1H), 3.96 (s, 3H ), 4.06−4.11 (m, 1H), 4.31 (d, J = 10 Hz, 1H), 4.54 (d, J = ll Hz, 1H), 4.72−4.77 (m, 1H), 5.23 (d, J = 10 Hz, 1H), 5.34 (m, 1H), 6.96 (s, 1H), 7.07 (dd, J = 9, 2 Hz, 1H), 7.44−7.52 (m, 3H), 7.99−8.03 (m, 3H .) LC-MS (retention time: 1.43, method A) MS m / e 592 ( M + + l).

Then 1- (2-tert-butoxycarbonyl-amino-3,3-dimethylbutyryl) -4- (7- in THF (318 mL), CH ₃ 0H (42 mL) and H ₂ 0 (170 mL). To a solution of methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2-carboxylic acid methyl ester (4.179 g, 7.06 mmol) was added LiOH (1.356 g, 56.5 mmol). The reaction mixture is stirred for 1 day, acidified to neutral pH, concentrated in vacuo until only the aqueous layer remains, the resulting aqueous residue is acidified by adding 1.0 N aqueous HCl to pH 4.0, and solid NaCl. Saturated with This aqueous mixture was repeatedly extracted with 80% EtOAc / THF (4 × 300 mL) and the combined organic solvents were dried (MgSO ₄ ), filtered, concentrated in vacuo, and 3.69 g (91 %). ¹ H NMR (CDCl ₃ ) δ 1.03 (s, 9H), 1.27 (s, 9H), 2.36-2.43 (m, 1H), 2.78-2.83 (m, 1H), 3.94 (s, 3H), 4.05 (d, J = 10 Hz, 1H), 4.24 (d, J = 9 Hz, 1H), 4.54 (d, J = 12 Hz, 1H), 4.63−4.67 (m, 1H), 5.52 (m, 1H) , 7.09 (dd, J = 9 Hz, 1H), 7.20 (s, 1H), 7.38 (s, 1H), 7.51−7.55 (m, 3H), 7.99−8.00 (m, 3H), 8.09 (d, J LC-MS (retention time: 1.44, method A), MS m / z 578 (M ⁺ +1).

具体的には、１−アミノシクロブタンカルボン酸(100 mg, 0.869 mmol)(Tocris)をMeOH10 mLに溶解させ、ＨＣlガスを2h吹き込んだ。反応混合物を18 h攪拌し、ついで真空にて濃縮し、黄色油状物質144 mgを得た。エーテル10 mLでトリチュレートし、白色固体の標題化合物100 mgを得た。¹Ｈ ＮＭＲ(CDC1₃) δ 2.10−2.25 (m, 1H), 2.28−2.42 (m, 1H), 2.64−2.82 (m, 4H), 3.87 (s, 3H), 9.21 (br s, 3H). In Step 25b, 1-aminocyclobutanecarboxylic acid / hydrochloride (described below) was produced.

Specifically, 1-aminocyclobutanecarboxylic acid (100 mg, 0.869 mmol) (Tocris) was dissolved in 10 mL of MeOH, and HCl gas was blown in for 2 h. The reaction mixture was stirred for 18 h and then concentrated in vacuo to give 144 mg of a yellow oil. Trituration with 10 mL of ether gave 100 mg of the title compound as a white solid. ¹ H NMR (CDC1 ₃ ) δ 2.10-2.25 (m, 1H), 2.28-2.42 (m, 1H), 2.64-2.82 (m, 4H), 3.87 (s, 3H), 9.21 (br s, 3H).

In step 25c, the product 1-{[1- (2-tert-butoxycarbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine- 2-carbonyl] amino} -cyclobutanecarboxylic acid (below), also known as BOC P3- (1-tBuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline) ] -P1- (1- aminocyclobutane-1) and the CO ₂ Me produced using two consecutive steps.

1- (2-tert-Butoxycarbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carboxylic acid (2 mL) in 2 mL of methylene chloride 100 mg, 0.173 mmol), DIPEA (112 mg, 0.865 mmol), then HBTU (78.4 mg, 0.207), HOBT-H20 (32 mg, 0.207 mmol), and finally 1-aminocyclobutane-carboxylic acid Methyl ester-hydrochloride (30 mg, 0.182 mmol) was added. The mixture was 24 h stirring at rt, diluted with EtOAc (50 mL), saturated aqueous NaHC0 ₃ (25 mL), washed with brine (25 mL), dried (MgSO4), filtered and in vacuo Concentration gave 134 mg of a crude product as a yellow oil. Flash chromatography, eluting with 1: 1 ethyl acetate / hexane, 93 mg (78%) of 1-{[1- (2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)- 4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] amino} cyclobutane-carboxylic acid methyl ester, also known as BOC P3- (1-tBuGly) -P2 [(4R)-( 2-phenyl-7-methoxy - quinoline-4-oxo) - proline)] - P1- (1-amino-cyclobutane-l) to give CO ₂ Me, the. ¹ H NMR (CDC1 ₃ ) δ 1.06 (s, 9H), 1.43 (s, 9H), 1.98−2.09 (m, 2H), 2.23−2.32 (m, 2H), 2.42−2.50 (m, 1H), 2.61 −2.71 (m, 2H), 2.93−3.02 (m, 1H), 3.74 (s, 3H), 3.96 (s, 3H), 4.37 (d, J = 12 Hz, 1H), 4.47 (d, J = 9 Hz, 1H), 4.87 (t, J = 7 Hz, 1H), 5.23−5.26 (d, J = 9.8 Hz, 1H), 5.36 (brs, 1H), 7.04−7.08 (m, 2H), 7.45−7.54 (m, 5H), 8.05-8.08 (m, 3H); LC-MS (retention time: 1.67 min, method D), MS m / z 689 (M ⁺ +1). HPLC retention time: 13.42 min.

1-{[1- (2-tert-Butoxycarbonyl-amino-3,3-dimethylbutyryl) -4- (7-methoxy-) in THF (3 mL), methanol (1.5 mL) and water (0.4 mL). 2-Phenylquinolin-4-yloxy) pyrrolidine-2-carbonyl] -amino} -cyclobutane-carboxylic acid methyl ester (2) (93 mg, 0.135 mmol) in a mixture of 30 mg LiOH (65 mg, 2.7 mmol) Was added. The mixture was stirred at rt for 3 days, concentrated in vacuo, then partitioned between ether (50 mL) and water (25 mL). The aqueous layer was acidified with 1N HCl to pH 4 and extracted with ether (3 × 50 mL). The combined ether layers were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 81 mg (89%) of the title compound as a white foam. ¹ H NMR (CDC1 ₃ ) δ 1.04 (s, 9H), 1.41 (s, 9H), 1.98−2.09 (m, 2H), 2.20−2.30 (m, 2H), 2.50−2.58 (m, 1H), 2.66 −2.80 (m, 2H), 2.84−2.93 (m, 1H), 3.98 (s, 3H), 4.31 (d, J = 9 Hz, 1H), 4.54 (d, J = 10 Hz, 1H), 4.83 ( t, J = 7 Hz, 1H), 5.28 (d, J = 12 Hz, 1H), 5.39 (br s, 1H), 7.03 (s, 1H), 7.08 (dd, J = 3, 9 Hz, 1H) , 7.47−7.55 (m, 4H), 7.64 (br s, 1H), 8.06−8.08 (m, 3H). LC-MS (retention time: 1.66, method D), MS m / z 675 (M ⁺ +1 HPLC retention time: 11.06 min.

In step 25d, compound 22 was prepared from a mixture of 64 mg (0.095 mmol) of the product of step 25c and CDI (19.9 mg, 0.123 mmol) by heating at reflux for 1 h. After cooling the reaction mixture to rt, cyclopropylsulfonamide (14.9 mg, 0.123 mmol) was added followed by DBU (18.7 mg, 0.123 mmol). After stirring at rt for 24 h, the reaction was partitioned between EtOAc (50 mL) and pH 4 buffer (25 mL). The organic phase was washed with saturated NaHCO ₃ solution (25 mL), dried (MgSO _4), filtered, and concentrated in vacuo. The crude product was purified on an Analtech 1000p 20 x 40 cm PTLC plate (eluted twice with 2.5% methanol in methylene chloride) to give 30 mg (41%) of compound 22 as a white solid. LC-MS (retention time: 1.67, method D) MS m / z 778 (M ⁺ +1). HPLC retention time: 12.03 min.

ＬＣ／ＭＳ rt−min (MH⁺): 1.86 (806) (方法D). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 0.89 (t, J=7. 3 Hz, 1H), 1.04 (s, 9H), 1.26−1.44 (m, 12H), 1.67−1.73 (m, 2H), 1.78−1.80 (m, 1H), 2.01−2.09 (m, 1H), 2.53 (m, 1H), 2.68−2.72 (m, 1H), 3.06−3.17 (m, 2H), 3.92, 3.94 (2s, 3H), 4.15−4.18 (m, 1H), 4.25 (s, 1H), 4.49−4.55 (m, 2H), 5.00 (d, J=10 Hz, 1H), 5.18 (d, J=17 Hz, 1H), 5.53 (m, 1H), 5.82−5.90 (m, 1H), 7.06 (dd, J=9, 2 Hz, 1H), 7.25 (s, 1H), 7.36−7.38 (m, 1H), 7.46−7.554 (m, 3H), 8.04−8.09 (m, 3H). Example 26
The following compounds of the invention were also prepared by the methods described in Examples 1-25 above.
Compound 23

LC / MS rt-min (MH ⁺ ): 1.86 (806) (Method D). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 0.89 (t, J = 7.3 Hz, 1H), 1.04 (s , 9H), 1.26−1.44 (m, 12H), 1.67−1.73 (m, 2H), 1.78−1.80 (m, 1H), 2.01−2.09 (m, 1H), 2.53 (m, 1H), 2.68−2.72 (m, 1H), 3.06−3.17 (m, 2H), 3.92, 3.94 (2s, 3H), 4.15−4.18 (m, 1H), 4.25 (s, 1H), 4.49−4.55 (m, 2H), 5.00 (d, J = 10 Hz, 1H), 5.18 (d, J = 17 Hz, 1H), 5.53 (m, 1H), 5.82-5.90 (m, 1H), 7.06 (dd, J = 9, 2 Hz, 1H), 7.25 (s, 1H), 7.36−7.38 (m, 1H), 7.46−7.554 (m, 3H), 8.04−8.09 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.79 (790) (方法D). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 0.74 (t, J=7.3 Hz, 3H), 1.08 (s, 9H), 0.79−1.29 (m, 10H), 1.34−1.42 (m, 1H), 2.00−2.15 (m, 2H), 2.28−2.35 (m, 1H), 2.39−2.44 (m, 1H), 2.65 (dd, J=14,6 Hz, 1H), 3.99 (s, 3H), 4.13 (d, J=12 Hz, 1H), 4.22 (d, J=ll Hz, 1H), 4.28 (dd, J=12, 4 Hz, 1H), 4.57−4.61 (m, 1H), 5.00 (d, J=ll Hz, 1H), 5.13 (d, J=17 Hz, 1H), 5.51 (m, 1H), 5.92−5.99 (m, 1H), 6.73 (d, J=9 Hz, NH), 7.20 (s, 1H), 7.42 (d, J=2 Hz, 1H), 7.48−7.56 (m, 4H), 7.82 (d, J=9 Hz, 1H), 8.03−8.04 (m, 3H). Compound 24

LC / MS rt-min (MH ⁺ ): 1.79 (790) (Method D). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 0.74 (t, J = 7.3 Hz, 3H), 1.08 (s, 9H ), 0.79-1.29 (m, 10H), 1.34-1.42 (m, 1H), 2.00-2.15 (m, 2H), 2.28-2.35 (m, 1H), 2.39-2.44 (m, 1H), 2.65 (dd , J = 14,6 Hz, 1H), 3.99 (s, 3H), 4.13 (d, J = 12 Hz, 1H), 4.22 (d, J = ll Hz, 1H), 4.28 (dd, J = 12, 4 Hz, 1H), 4.57−4.61 (m, 1H), 5.00 (d, J = ll Hz, 1H), 5.13 (d, J = 17 Hz, 1H), 5.51 (m, 1H), 5.92−5.99 ( m, 1H), 6.73 (d, J = 9 Hz, NH), 7.20 (s, 1H), 7.42 (d, J = 2 Hz, 1H), 7.48-7.56 (m, 4H), 7.82 (d, J = 9 Hz, 1H), 8.03−8.04 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.84 (778) (方法D). ¹Ｈ ＮＭＲ：(メタノール−d₄ 500MHz) δ 1.03 (s, 9H), 1.24−1.38 (m, 3H), 1.26 (s, 9H), 1.83 (m, 1H), 2.09−2.18 (m, 1H), 2.41 (m, 1H), 2.66−2.77 (m, 1H), 3.03−3.30 (m, 2H), 3.93 (s, 3H), 4.02−4.14 (m, 1H), 4.25 (m, 1H), 4.51−4.57 (m, 2H), 5.05 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.53 (m, 1H), 5.75−5.89 (m, 1H), 7.06 (d, J=9 Hz, 1H), 7.24 (s, 1H), 7.37 (s, 1H), 7.47−7.54 (m, 3H), 8.03−8.10 (m, 3H). Compound 25

LC / MS rt-min (MH ⁺ ): 1.84 (778) (Method D). ¹ H NMR: (Methanol-d ₄ 500 MHz) δ 1.03 (s, 9H), 1.24-1.38 (m, 3H), 1.26 ( s, 9H), 1.83 (m, 1H), 2.09−2.18 (m, 1H), 2.41 (m, 1H), 2.66−2.77 (m, 1H), 3.03−3.30 (m, 2H), 3.93 (s, 3H), 4.02−4.14 (m, 1H), 4.25 (m, 1H), 4.51−4.57 (m, 2H), 5.05 (d, J = 10 Hz, 1H), 5.23 (d, J = 17 Hz, 1H ), 5.53 (m, 1H), 5.75−5.89 (m, 1H), 7.06 (d, J = 9 Hz, 1H), 7.24 (s, 1H), 7.37 (s, 1H), 7.47−7.54 (m, 3H), 8.03-8.10 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.85 (792) (方法D). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.04 (s, 9H), 1.26−1.30 (m, 12H), 1.34 (m, 1H), 1.56−1.66 (m, 1H), 1.69−1. 83 (m, 2H), 2.00−2.11 (m, 1H), 2.46−2.55 (m, 1H), 2.64−2.73 (m, 1H), 3.13−3.19 (m, 2H), 3.93 (s, 3H), 4.12−4.18 (m, 1H), 4.25 (m, 1H), 4.50−4.58 (m, 2H), 5.01 (d, J=10 Hz, 1H), 5.19 (d, J=17 Hz, 1H), 5.54 (m, 1H), 5.80−5.92 (m, 1H), 7.06 (d, J=9 Hz, 1H), 7.25 (s, 1H), 7.37 (m, 1H), 7.47−7.55 (m, 3H), 8.04−8.12 (m, 3H). Compound 26

LC / MS rt-min (MH ⁺ ): 1.85 (792) (Method D). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.04 (s, 9H), 1.26-1.30 (m, 12H), 1.34 (m, 1H), 1.56-1.66 (m, 1H), 1.69-1.83 (m, 2H), 2.00−2.11 (m, 1H), 2.46−2.55 (m, 1H), 2.64−2.73 (m, 1H), 3.13−3.19 (m, 2H), 3.93 (s, 3H), 4.12−4.18 (m, 1H), 4.25 (m, 1H), 4.50−4.58 (m, 2H), 5.01 (d, J = 10 Hz, 1H), 5.19 (d, J = 17 Hz, 1H), 5.54 (m, 1H), 5.80−5.92 (m, 1H), 7.06 (d, J = 9 Hz, 1H), 7.25 (s, 1H), 7.37 (m, 1H), 7.47−7.55 (m, 3H), 8.04−8.12 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.80 (792) (方法D). Compound 27

LC / MS rt-min (MH ⁺ ): 1.80 (792) (Method D).

ＬＣ／ＭＳ rt−min (MH⁺): 1.57 (690) (方法D). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.04−1.33 (m, 4H), 1.17 (s, 9H), 1.42 (m, 1H), 1.89 (m, 1H), 2.33 (m, 1H), 2.43 (m, 1H), 2.84 (m, 1H), 2.95 (s, 1H), 4.06 (s, 3H), 4.19 (m, 2H), 4.56 (m, 1H), 4.76 (m, 1H), 5.13 (d, J=10 Hz, 1H), 5.32 (d, J=17 Hz, 1H), 5.65−5.76 (m, 1H), 5.90 (m, 1H), 7.47 (m, 1H), 7.63 (s, 2H), 7.74 (m, 3H), 8.15 (m, 2H), 8.48 (m, 1H). Compound 28

LC / MS rt-min (MH ⁺ ): 1.57 (690) (Method D). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.04-1.33 (m, 4H), 1.17 (s, 9H), 1.42 (m, 1H), 1.89 (m, 1H), 2.33 (m, 1H), 2.43 (m, 1H), 2.84 (m, 1H), 2.95 (s, 1H), 4.06 (s, 3H), 4.19 ( m, 2H), 4.56 (m, 1H), 4.76 (m, 1H), 5.13 (d, J = 10 Hz, 1H), 5.32 (d, J = 17 Hz, 1H), 5.65−5.76 (m, 1H ), 5.90 (m, 1H), 7.47 (m, 1H), 7.63 (s, 2H), 7.74 (m, 3H), 8.15 (m, 2H), 8.48 (m, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.57 (802) (方法D). ¹Ｈ ＮＭＲ: (CDC1₃, 500MHz) δ 0.94−1.78 (m, 13H), 1.07 (s, 9H), 1.87−2.03 (m, 2H), 2.16−2.19 (m, 1H), 2.32−2.45 (m, 2H), 2.64−2.68 (m, 1H), 3.91−3.96 (m, 1H), 3.96 (s, 3H), 4.06 (d, J=12 Hz, 1H), 4.20 (dd, J=12, 4 Hz, 1H), 4.56−4.60 (m, 1H), 4.98−5.01 (m, 1H), 5.13−5.16 (m, 1H), 5.29 (m, 1H), 6.01−6.08 (m, 1H), 6.88 (s, 1H), 6.92 (dd, J=9, 2 Hz, 1H), 7.42−7.51 (m, 4H), 7.86 (d, J=9 Hz, 1H), 7.99−8.03 (m, 2H). Compound 29

LC / MS rt-min (MH ⁺ ): 1.57 (802) (Method D). ¹ H NMR: (CDC1 ₃ , 500 MHz) δ 0.94-1.78 (m, 13H), 1.07 (s, 9H), 1.87−2.03 (m, 2H), 2.16−2.19 (m, 1H), 2.32−2.45 (m, 2H), 2.64−2.68 (m, 1H), 3.91−3.96 (m, 1H), 3.96 (s, 3H), 4.06 (d, J = 12 Hz, 1H), 4.20 (dd, J = 12, 4 Hz, 1H), 4.56−4.60 (m, 1H), 4.98−5.01 (m, 1H), 5.13−5.16 (m, 1H ), 5.29 (m, 1H), 6.01−6.08 (m, 1H), 6.88 (s, 1H), 6.92 (dd, J = 9, 2 Hz, 1H), 7.42−7.51 (m, 4H), 7.86 ( d, J = 9 Hz, 1H), 7.99−8.03 (m, 2H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.90 (804) (方法D). ¹Ｈ ＮＭＲ: (CDC1₃, 500MHz) δ 1.20−1.34 (m, 10H), 1.30 (s, 9H), 1.39−1.42 (m, 1H), 1.44−1.55 (m, 2H), 1.55−1.64 (m, 2H), 1.64−1.75 (m, 2H), 1.92 (dd, J=8, 6 Hz, 1H), 2.25−2.30 (m, 1H), 2.39−2.44 (m, 1H), 2.58−2.62 (m, 1H), 3.76−3.82 (m, 1H), 3.93 (s, 3H), 4.03 (dd, J=12, 4 Hz, 1H), 4.19 (t, J=9 Hz, 1H), 4.49 (dd, J= 9,7 Hz, 1H), 4.64 (d, J=12 Hz, 1H), 5. 09 (d, J=ll Hz, 1H), 5.20 (d, J=17 Hz, 1H), 5.32 (m, 1H), 5.54 (d, J=8 Hz, 1H), 5.73−5.80 (m, 1H), 6.94 (s, 1H), 7.01 (dd, J=9, 2 Hz, 1H), 7.41−7.50 (m, 4H), 7.98−8.00 (m, 3H). Compound 30

LC / MS rt−min (MH ⁺ ): 1.90 (804) (Method D). ¹ H NMR: (CDC1 ₃ , 500 MHz) δ 1.20−1.34 (m, 10H), 1.30 (s, 9H), 1.39−1.42 (m, 1H), 1.44−1.55 (m, 2H), 1.55−1.64 (m, 2H), 1.64−1.75 (m, 2H), 1.92 (dd, J = 8, 6 Hz, 1H), 2.25−2.30 (m, 1H), 2.39−2.44 (m, 1H), 2.58−2.62 (m, 1H), 3.76−3.82 (m, 1H), 3.93 (s, 3H), 4.03 (dd, J = 12, 4 Hz , 1H), 4.19 (t, J = 9 Hz, 1H), 4.49 (dd, J = 9,7 Hz, 1H), 4.64 (d, J = 12 Hz, 1H), 5.09 (d, J = ll Hz, 1H), 5.20 (d, J = 17 Hz, 1H), 5.32 (m, 1H), 5.54 (d, J = 8 Hz, 1H), 5.73−5.80 (m, 1H), 6.94 (s, 1H), 7.01 (dd, J = 9, 2 Hz, 1H), 7.41-7.50 (m, 4H), 7.98-8.00 (m, 3H).

ＬＣ／ＭＳ rt−min (MH+): 1.80 (776) (方法D). Compound 31

LC / MS rt-min (MH +): 1.80 (776) (Method D).

ＬＣ／ＭＳ rt−min (MH⁺): 1.85 (778) (方法D). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 0.87 (d, J= 7 Hz, 1H), 1.06−1.08 (m, 9H), 1.29−1.37 (m, 10H), 1.96−2.06 (m, 1H), 2.04−2.12 (m, 1H), 2.27−2.40 (m, 1H), 2.64−2.68 (m, 1H), 2.94−2.99 (m, 1H), 3.76 (d, J=11. 0 Hz, 1H), 3.94, 3.96 (2s, 3H), 4.07 (d, J=11. 6 Hz, 1H), 4.18 (dd, J=11. 6,4.6 Hz, 1H), 4.63 (dd, J=10. 7,6.4 Hz, 1H), 4.99 (dd, J=10. 4,1.6 Hz, 1H), 5.31 (m, 1H), 6.01−6. 09 (m, 1H), 6.94 (dd, J=9, 2.4 Hz, 1H), 7.43 (d, J=2. 4 Hz, 1H), 7.46−7.54 (m, 4H), 7.89 (d, J=9. 1 Hz, 1H), 7.98−8.03 (m, 2H). Compound 32

LC / MS rt-min (MH ⁺ ): 1.85 (778) (Method D). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 0.87 (d, J = 7 Hz, 1H), 1.06-1.08 (m , 9H), 1.29-1.37 (m, 10H), 1.96−2.06 (m, 1H), 2.04−2.12 (m, 1H), 2.27−2.40 (m, 1H), 2.64−2.68 (m, 1H), 2.94 −2.99 (m, 1H), 3.76 (d, J = 11.0 Hz, 1H), 3.94, 3.96 (2s, 3H), 4.07 (d, J = 11.6 Hz, 1H), 4.18 (dd, J = 11.6,4.6 Hz, 1H), 4.63 (dd, J = 10.7,6.4 Hz, 1H), 4.99 (dd, J = 10.4,1.6 Hz, 1H), 5.31 (m, 1H), 6.01−6.09 (m, 1H), 6.94 (dd, J = 9, 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.46−7.54 (m, 4H), 7.89 ( d, J = 9.1 Hz, 1H), 7.98−8.03 (m, 2H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.87 (790) (方法D). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 0.84 (d, J=6.4 Hz, 3H), 1.14−1.19 (m, 2H), 0.89−0.94 (m, 6H), 1.28 (s, 9H), 1.51 (m, 1H), 1.61−1.75 (m, 2H), 2.01−2.07 (m, 2H), 2.32−2.36 (m, 1H), 2.49 (m, 1H), 2.68 (dd, J=13.9, 6.3 Hz, 1H), 3.90, 4.01 (2s, 3H), 4.11 (d, J=11. 9 Hz, 1H), 4.20 (dd, J=11. 9,3.4 Hz, 1H), 4.54−4.60 (m, 2H), 4.99 (d, J=11. 0 Hz, 1H), 5.13 (d, J=17.4 Hz, 1H), 5.53, 5.57 (m, 1H), 5.87−5.97 (m, 1H), 6.87 (d, J=7.6 Hz, 1H), 7.23 (s, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.47−7.55 (m, 4H), 7.86 (d, J=8.6 Hz, 1H), 8.02−8.07 (m, 3H). Compound 33

LC / MS rt-min (MH ⁺ ): 1.87 (790) (Method D). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 0.84 (d, J = 6.4 Hz, 3H), 1.14-1.19 (m , 2H), 0.89−0.94 (m, 6H), 1.28 (s, 9H), 1.51 (m, 1H), 1.61−1.75 (m, 2H), 2.01−2.07 (m, 2H), 2.32−2.36 (m , 1H), 2.49 (m, 1H), 2.68 (dd, J = 13.9, 6.3 Hz, 1H), 3.90, 4.01 (2s, 3H), 4.11 (d, J = 11.9 Hz, 1H), 4.20 ( dd, J = 11, 9,3.4 Hz, 1H), 4.54−4.60 (m, 2H), 4.99 (d, J = 11.0 Hz, 1H), 5.13 (d, J = 17.4 Hz, 1H), 5.53 , 5.57 (m, 1H), 5.87−5.97 (m, 1H), 6.87 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.47− 7.55 (m, 4H), 7.86 (d, J = 8.6 Hz, 1H), 8.02−8.07 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.93 (792) (方法D). Compound 34

LC / MS rt-min (MH ⁺ ): 1.93 (792) (Method D).

ＬＣ／ＭＳ rt−min (MH⁺): 1. 65 (877) (方法B). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.06 (s, 9H), 1.27 (s, 9H), 1.29−1.33 (m, 1H), 1.70−1.73 (m, 1H), 2.06−2.12 (m, 1H), 2.36 (m, 1H), 2.60−2.71 (m, 1H), 3.94 (s, 3H), 4.08−4.12 (m, 1H), 4.25−4.28 (m, 1H), 4.52−4.57 (m, 2H), 4.91 (d, J=11 Hz, 1H), 5.14 (d, J=17 Hz, 1H), 5.53 (m, 2H), 6.97−7.08 (m, 4H), 7.24 (s, 1H), 7.39 (s, 1H), 7.47−7. 55 (m, 3H), 7.81−7.88 (m, 4H), 8.04−8.09 (m, 3H). Compound 35

LC / MS rt-min (MH ⁺ ): 1. 65 (877) (Method B). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.06 (s, 9H), 1.27 (s, 9H), 1.29 −1.33 (m, 1H), 1.70−1.73 (m, 1H), 2.06−2.12 (m, 1H), 2.36 (m, 1H), 2.60−2.71 (m, 1H), 3.94 (s, 3H), 4.08 −4.12 (m, 1H), 4.25−4.28 (m, 1H), 4.52−4.57 (m, 2H), 4.91 (d, J = 11 Hz, 1H), 5.14 (d, J = 17 Hz, 1H), 5.53 (m, 2H), 6.97−7.08 (m, 4H), 7.24 (s, 1H), 7.39 (s, 1H), 7.47−7.55 (m, 3H), 7.81−7.88 (m, 4H), 8.04−8.09 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.73 (841) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.06 (s, 9H), 1.28 (s, 9H), 1.32−1.35 (m, 1H), 1.69 (dd, J=8, 5.5 Hz, 1H), 2.11−2.18 (m, 1H), 2.31−2.37 (m, 1H), 2.40 (s, 3H), 2.62 (dd, J=14,7 Hz, 1H), 3.95 (s, 3H), 4.08−4.13 (m, 1H), 4.25−4.29 (m, 1H), 4.52−4.57 (m, 2H), 4.92 (d, J=12 Hz, 1H), 5.16 (d, J=17 Hz, 1H), 5.37−5.46 (m, 1H), 5.58 (m, 1H),), 7.10 (dd, J=9,2 Hz, 1H), 7.27 (2s, 1H), 7.38−7.42 (m, 2H), 7.44−7.47 (m, 1H), 7.49−7.58 (m, 3H), 7.77 (m, 2H), 8.04, 8.06 (2s, 2H), 8.10 (d, J=9 Hz, 1H). Compound 36

LC / MS rt-min (MH ⁺ ): 1.73 (841) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.06 (s, 9H), 1.28 (s, 9H), 1.32–1.35 (m, 1H), 1.69 (dd, J = 8, 5.5 Hz, 1H), 2.11−2.18 (m, 1H), 2.31−2.37 (m, 1H), 2.40 (s, 3H), 2.62 (dd, J = 14,7 Hz, 1H), 3.95 (s, 3H), 4.08−4.13 (m, 1H), 4.25−4.29 (m, 1H), 4.52−4.57 (m, 2H), 4.92 (d, J = 12 Hz, 1H), 5.16 (d, J = 17 Hz, 1H), 5.37−5.46 (m, 1H), 5.58 (m, 1H),), 7.10 (dd, J = 9,2 Hz, 1H), 7.27 (2s, 1H), 7.38-7.42 (m, 2H), 7.44-7.47 (m, 1H), 7.49-7.58 (m, 3H), 7.77 (m, 2H), 8.04, 8.06 (2s, 2H), 8.10 (d, J = 9 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.59 (841) (方法B). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.04 (s, 9H), 1.26 (s, 9H), 1.21−1.43 (m, 1H), 1.72 (dd, J=7,5 Hz, 1H), 2.06−2.21 (m, 1H), 2.34 (m, 4H), 2.56−2.72 (m, 1H), 3.93 (s, 3H), 4.05−4.11 (m, 1H), 4.25 (s, 1H), 4.48−4.55 (m, 2H), 4.90 (d, J=ll Hz, 1H), 5.13 (d, J=17 Hz, 1H), 5.40−5.87 (m, 2H), 7.06 (dd, J=9,2 Hz, 1H), 7.18−7.25 (m, 3H), 7.37 (d, J=2 Hz, 1H), 7.46−7.53 (m, 3H), 7.80 (d, J=8.2, 2H), 8.03−8.10 (m, 3H). Compound 37

LC / MS rt-min (MH ⁺ ): 1.59 (841) (Method B). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.04 (s, 9H), 1.26 (s, 9H), 1.21-1.43 (m, 1H), 1.72 (dd, J = 7,5 Hz, 1H), 2.06−2.21 (m, 1H), 2.34 (m, 4H), 2.56−2.72 (m, 1H), 3.93 (s, 3H ), 4.05−4.11 (m, 1H), 4.25 (s, 1H), 4.48−4.55 (m, 2H), 4.90 (d, J = ll Hz, 1H), 5.13 (d, J = 17 Hz, 1H) , 5.40−5.87 (m, 2H), 7.06 (dd, J = 9,2 Hz, 1H), 7.18−7.25 (m, 3H), 7.37 (d, J = 2 Hz, 1H), 7.46−7.53 (m , 3H), 7.80 (d, J = 8.2, 2H), 8.03−8.10 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.66 (826) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.06 (s, 9H), 1.28 (s, 9H), 1. 31−1.34 (m, 1H), 1.71 (dd, J=8, 5.5 Hz, 1H), 2.11−2.16 (m, 1H), 2.30−2.39 (m, 1H), 2.64−2.72 (m, 1H), 3.95 (s, 3H), 4.11 (dd, J=12, 2.6 Hz, 1H), 4.25−4.29 (m, 1H), 4.52−4.57 (m, 2H), 4.91 (d, J=10 Hz, 1H), 5.15 (d, J=17 Hz, 1H), 5.37−5.46 (m, 1H), 5.57 (m, 1H), 7.10 (dd, J=9,2 Hz, 1H), 7.27 (s, 1H), 7.40 (d, J=2 Hz, 1H), 7.49−7. 58 (m, 5H), 7.61−7. 65 (m, 1H), 7.96−7.97 (m, 2H), 8.04,8.05 (2s, 2H), 8.10 (d, J=9 Hz, 1H). Compound 38

LC / MS rt-min (MH ⁺ ): 1.66 (826) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.06 (s, 9H), 1.28 (s, 9H), 1. 31 −1.34 (m, 1H), 1.71 (dd, J = 8, 5.5 Hz, 1H), 2.11−2.16 (m, 1H), 2.30−2.39 (m, 1H), 2.64−2.72 (m, 1H), 3.95 (s, 3H), 4.11 (dd, J = 12, 2.6 Hz, 1H), 4.25−4.29 (m, 1H), 4.52−4.57 (m, 2H), 4.91 (d, J = 10 Hz, 1H), 5.15 (d, J = 17 Hz, 1H), 5.37−5.46 (m, 1H), 5.57 (m, 1H), 7.10 (dd, J = 9,2 Hz, 1H), 7.27 (s, 1H), 7.40 (d, J = 2 Hz, 1H), 7.49-7.58 (m, 5H), 7.61-7.65 (m, 1H), 7.96-7.97 (m, 2H), 8.04,8.05 (2s, 2H) , 8.10 (d, J = 9 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.73 (895) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.03 (s, 9H), 1.26 (s, 9H), 1.32 (m, 1H), 1.69−1.73 (m, 1H), 2.00−2.06 (m, 1H), 2.43−2.50 (m, 1H), 2.56−2.60 (m, 1H), 3.93 (s, 3H), 4.04−4.17 (m, 1H), 4.22 (s, 1H), 4.45 (d, J=12 Hz, 1H), 4.52 (t, J=8. 5 Hz, 1H), 4.84 (d, J=10 Hz, 1H), 5.09 (d, J=17 Hz, 1H), 5.46 (m, 1H), 5.70 (m, 1H), 7.04−7.25 (m, 4H), 7.33−7.40 (m, 2H), 7.47−7.57 (m, 3H), 8.02−8.11 (m, 3H). Compound 39

LC / MS rt-min (MH ⁺ ): 1.73 (895) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.03 (s, 9H), 1.26 (s, 9H), 1.32 (m , 1H), 1.69−1.73 (m, 1H), 2.00−2.06 (m, 1H), 2.43−2.50 (m, 1H), 2.56−2.60 (m, 1H), 3.93 (s, 3H), 4.04−4.17 (m, 1H), 4.22 (s, 1H), 4.45 (d, J = 12 Hz, 1H), 4.52 (t, J = 8.5 Hz, 1H), 4.84 (d, J = 10 Hz, 1H) , 5.09 (d, J = 17 Hz, 1H), 5.46 (m, 1H), 5.70 (m, 1H), 7.04−7.25 (m, 4H), 7.33−7.40 (m, 2H), 7.47−7.57 (m , 3H), 8.02−8.11 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.66 (851) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) 8 1.02 (s, 9H), 1.26 (s, 9H), 1.31 (m, 1H), 1.74 (dd, J=7, 5 Hz, 1H), 2.05−2.11 (m, 1H), 2.46 (m, 1H), 2.61−2.73 (m, 1H), 3.91, 3.94 (2s, 3H), 4.06−4.11 (m, 1H), 4.22 (s, 1H), 4.48 (d, J=12 Hz, 1H), 4.56 (t, J=9 Hz, 1H), 4.90−4.95 (m, 1H), 5.14 (d, J=17 Hz, 1H), 5.48 (m, 1H), 5.69−5.76 (m, 1H), 7.02−7.08 (m, 1H), 7.21 (s, 1H), 7.35−7.39 (m, 1H), 7.47−7.59 (m, 3H), 7.76−7.79 (m, H), 8.01−0.22 (m, 5H). Compound 40

LC / MS rt-min (MH ⁺ ): 1.66 (851) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) 8 1.02 (s, 9H), 1.26 (s, 9H), 1.31 (m , 1H), 1.74 (dd, J = 7, 5 Hz, 1H), 2.05−2.11 (m, 1H), 2.46 (m, 1H), 2.61−2.73 (m, 1H), 3.91, 3.94 (2s, 3H ), 4.06−4.11 (m, 1H), 4.22 (s, 1H), 4.48 (d, J = 12 Hz, 1H), 4.56 (t, J = 9 Hz, 1H), 4.90−4.95 (m, 1H) , 5.14 (d, J = 17 Hz, 1H), 5.48 (m, 1H), 5.69−5.76 (m, 1H), 7.02−7.08 (m, 1H), 7.21 (s, 1H), 7.35−7.39 (m , 1H), 7.47-7.59 (m, 3H), 7.76-7.79 (m, H), 8.01-0.22 (m, 5H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.65 (851) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.02 (s, 9H), 1. 26 (s, 9H), 1.21−1.30 (m, 1H), 1.73 (dd, J=7, 5 Hz, 1H), 2.03−2.09 (m, 1H), 2.41−2.50 (m, 1H), 2.62−2.69 (m, 1H), 3.92, 3.94 (2s, 3H), 4.07−4.11 (m, 1H), 4.22 (s, 1H), 4.48 (d, J=12 Hz, 2H), 4.52−4.59 (m, 1H), 5.13 (d, J=17 Hz, 1H), 5.48 (m, 1H), 5.72−5.80 (m, 1H), 7.04 (dd, J=9, 2 Hz, 1H), 7.21 (s, 1H), 7.35−7.39 (m, 1H), 7.46−7.54 (m, 3H), 7.73 (m, 2H), 7.89−8.10 (m, 5H). Compound 41

LC / MS rt-min (MH ⁺ ): 1.65 (851) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.02 (s, 9H), 1.26 (s, 9H), 1.21 −1.30 (m, 1H), 1.73 (dd, J = 7, 5 Hz, 1H), 2.03−2.09 (m, 1H), 2.41−2.50 (m, 1H), 2.62−2.69 (m, 1H), 3.92 , 3.94 (2s, 3H), 4.07−4.11 (m, 1H), 4.22 (s, 1H), 4.48 (d, J = 12 Hz, 2H), 4.52−4.59 (m, 1H), 5.13 (d, J = 17 Hz, 1H), 5.48 (m, 1H), 5.72−5.80 (m, 1H), 7.04 (dd, J = 9, 2 Hz, 1H), 7.21 (s, 1H), 7.35−7.39 (m, 1H), 7.46-7.54 (m, 3H), 7.73 (m, 2H), 7.89-8.10 (m, 5H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.70 (860) (方法B). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.04 (s, 9H), 1.27 (s, 9H), 1.31−1.35 (m, 1H), 1.71 (dd, J=8,5 Hz, 1H), 2.11−2.17 (m, 1H), 2.37−2. 44 (m, 1H), 2.67 (dd, J=14, 7 Hz, 1H), 3.95 (s, 3H), 4.12 (dd, J=11. 9,3.1 Hz, 1H), 4.24−4.27 (m, 1H), 4.53−4.60 (m, 2H), 4.81−4.84 (m, 1H), 5.12 (d, J=16. 2 Hz, 1H), 5.19−5.28 (m, 1H), 5.58 (s, 1H), 7.10 (dd, J=9, 2 Hz, 1H), 7.28 (s, 1H), 7.30 (d, J=2 Hz, lH), 7.42−7.47 (m, 1H), 7.50−7.59 (m, 5H), 8.04−8.13 (m, 4H). Compound 42

LC / MS rt-min (MH ⁺ ): 1.70 (860) (Method B). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.04 (s, 9H), 1.27 (s, 9H), 1.31-1.35 (m, 1H), 1.71 (dd, J = 8,5 Hz, 1H), 2.11−2.17 (m, 1H), 2.37−2.44 (m, 1H), 2.67 (dd, J = 14, 7 Hz , 1H), 3.95 (s, 3H), 4.12 (dd, J = 11.9, 3.1 Hz, 1H), 4.24−4.27 (m, 1H), 4.53−4.60 (m, 2H), 4.81−4.84 (m , 1H), 5.12 (d, J = 16.2 Hz, 1H), 5.19−5.28 (m, 1H), 5.58 (s, 1H), 7.10 (dd, J = 9, 2 Hz, 1H), 7.28 ( s, 1H), 7.30 (d, J = 2 Hz, lH), 7.42-7.47 (m, 1H), 7.50-7.59 (m, 5H), 8.04-8.13 (m, 4H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.63 (860) (方法B). Compound 43

LC / MS rt-min (MH ⁺ ): 1.63 (860) (Method B).

ＬＣ／ＭＳ rt−min (MH⁺): 1.78 (860) (方法B). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.06 (s, 9H), 1.27 (s, 9H), 1.30−1.34 (m, 1H), 1.72 (dd, J=8,'5. 5 Hz, 1H), 2.11−2.16 (m, 1H), 2.32−2.43 (m, 1H), 2.68 (dd, J=14, 7 Hz, 1H), 3.95 (s, 3H), 4.07−4.12 (m, 1H), 4.24−4.27 (m, 1H), 4.53−4.57 (m, 2H), 4.92 (d, J=10 Hz, 1H), 5.15 (d, J=17 Hz, 1H), 5.37−5.45 (m, 1H), 5.58 (m, 1H), 7.11 (d, J=9 Hz, 1H), 7.29 (s, 1H), 7.39 (s, 1H), 7.52−7.57 (m, 5H), 7.91−7.94 (m, 2H), 8.04, 8.05 (2s, 2H), 8.10−8.13 (m, 1H). Compound 44

LC / MS rt-min (MH ⁺ ): 1.78 (860) (Method B). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.06 (s, 9H), 1.27 (s, 9H), 1.30–1.34 (m, 1H), 1.72 (dd, J = 8, '5.5 Hz, 1H), 2.11−2.16 (m, 1H), 2.32−2.43 (m, 1H), 2.68 (dd, J = 14, 7 Hz, 1H), 3.95 (s, 3H), 4.07−4.12 (m, 1H), 4.24−4.27 (m, 1H), 4.53−4.57 (m, 2H), 4.92 (d, J = 10 Hz, 1H) , 5.15 (d, J = 17 Hz, 1H), 5.37−5.45 (m, 1H), 5.58 (m, 1H), 7.11 (d, J = 9 Hz, 1H), 7.29 (s, 1H), 7.39 ( s, 1H), 7.52-7.57 (m, 5H), 7.91-7.94 (m, 2H), 8.04, 8.05 (2s, 2H), 8.10-8.13 (m, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.82 (879) (方法B). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.06 (s, 9H), 1.26 (s, 9H), 1.33 (dd, J=9, 5 Hz, 1H), 1.73 (dd, J=8,5 Hz, 1H), 2.11−2.17 (m, 1H), 2.36−2.43 (m, 1H), 2.71 (dd, J=14, 7 Hz, 1H), 3.96 (s, 3H), 4.13 (dd, J=12, 3 Hz 1H), 4.25 (s, 1H), 4.53−4.58 (m, 2H), 4.94 (d, J=10 Hz, 1H), 5.17 (d, J=17 Hz, 1H), 5.46−5.53 (m, 1H), 5.60 (m, 1H), 7.13 (dd, J=9, 2 Hz, 1H), 7.31 (s, 1H), 7.37−7.42 (m, 2H), 7.53−7.58 (m, 3H), 7.92−7.95 (m, 1H), 8.04−8.06 (m, 3H), 8.13 (d, J=9. 5 Hz, 1H). Compound 45

LC / MS rt-min (MH ⁺ ): 1.82 (879) (Method B). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.06 (s, 9H), 1.26 (s, 9H), 1.33 (dd , J = 9, 5 Hz, 1H), 1.73 (dd, J = 8,5 Hz, 1H), 2.11−2.17 (m, 1H), 2.36−2.43 (m, 1H), 2.71 (dd, J = 14 , 7 Hz, 1H), 3.96 (s, 3H), 4.13 (dd, J = 12, 3 Hz 1H), 4.25 (s, 1H), 4.53−4.58 (m, 2H), 4.94 (d, J = 10 Hz, 1H), 5.17 (d, J = 17 Hz, 1H), 5.46−5.53 (m, 1H), 5.60 (m, 1H), 7.13 (dd, J = 9, 2 Hz, 1H), 7.31 (s , 1H), 7.37−7.42 (m, 2H), 7.53−7.58 (m, 3H), 7.92−7.95 (m, 1H), 8.04−8.06 (m, 3H), 8.13 (d, J = 9.5 Hz , 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.76 (858) (方法B). ¹Ｈ ＮＭＲ:(メタノール−d₄, 500MHz) δ 1.03 (s, 9H), 1.27 (s, 9H), 1.33 (dd, J=9.5, 5 Hz, 1H), 1.72 (dd, J=8,6 Hz, 1H), 2.12−2.18 (m, 1H), 2.36−2.43 (m, 1H), 2.58 (s, 3H), 2.70 (dd, J=14, 7 Hz, lH), 3.95 (s, 3H), 4.12 (dd, J=12, 3 Hz, 1H), 4.22−4.26 (m, 1H), 4.54−4.59 (m, 2H), 5.15 (d, J=17 Hz, 1H), 5.28−5.35 (m, 1H), 5.59 (m, 1H), 7.11 (dd, J=9, 2 Hz, 1H), 7.20−7.27 (m, 3H), 7.40 (d, LJ=2 Hz, 1H), 7.51−7. 57 (m, 3H), 7.72 (dd, J=9,3 Hz, 1H), 8.04, 8.05 (2s, 2H), 8.12 (d, J=9 Hz, 1H). Compound 46

LC / MS rt-min (MH ⁺ ): 1.76 (858) (Method B). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.03 (s, 9H), 1.27 (s, 9H), 1.33 (dd , J = 9.5, 5 Hz, 1H), 1.72 (dd, J = 8,6 Hz, 1H), 2.12−2.18 (m, 1H), 2.36−2.43 (m, 1H), 2.58 (s, 3H), 2.70 (dd, J = 14, 7 Hz, lH), 3.95 (s, 3H), 4.12 (dd, J = 12, 3 Hz, 1H), 4.22−4.26 (m, 1H), 4.54−4.59 (m, 2H), 5.15 (d, J = 17 Hz, 1H), 5.28-5.35 (m, 1H), 5.59 (m, 1H), 7.11 (dd, J = 9, 2 Hz, 1H), 7.20-7.27 (m , 3H), 7.40 (d, LJ = 2 Hz, 1H), 7.51-7.57 (m, 3H), 7.72 (dd, J = 9,3 Hz, 1H), 8.04, 8.05 (2s, 2H), 8.12 (d, J = 9 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.79 (894) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1. 05 (s, 9H), 1.26, 1.28 (2s, 9H), 1.31−1.34 (m, 1H), 1.72 (m, 1H), 2.08−2.16 (m, 1H), 2.37−2.42 (m, 1H), 2.68 (dd, J=14, 7 Hz, 1H), 3.96 (s, 3H), 4.13 (dd, J=12 Hz, 1H), 4.25 (s, 1H), 4.53−4.57 (m, 2H), 5.13 (d, J==17 Hz, 1H), 5.42−5.49 (m, 1H), 5.59 (m, 1H), 7.12 (d, J=9 Hz, 1H), 7.31 (s, 1H), 7.40 (s, 1H), 7.54−7.57 (m, 3H), 7.70−7.74 (m, 1H), 7.93 (d, J=7 Hz, 1H), 8.04, 8.05 (2s, 2H), 8.12−8.22 (m, 3H). Compound 47

LC / MS rt-min (MH ⁺ ): 1.79 (894) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1. 05 (s, 9H), 1.26, 1.28 (2s, 9H) , 1.31-1.34 (m, 1H), 1.72 (m, 1H), 2.08−2.16 (m, 1H), 2.37−2.42 (m, 1H), 2.68 (dd, J = 14, 7 Hz, 1H), 3.96 (s, 3H), 4.13 (dd, J = 12 Hz, 1H), 4.25 (s, 1H), 4.53−4.57 (m, 2H), 5.13 (d, J == 17 Hz, 1H), 5.42−5.49 (m, 1H), 5.59 (m, 1H), 7.12 (d, J = 9 Hz, 1H), 7.31 (s, 1H), 7.40 (s, 1H), 7.54−7.57 (m, 3H), 7.70− 7.74 (m, 1H), 7.93 (d, J = 7 Hz, 1H), 8.04, 8.05 (2s, 2H), 8.12−8.22 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.74 (894) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.01 (s, 9H), 1.26, 1.28 (2s, 9H), 1.30−1.33 (m, 1H), 1.72 (dd, J=8,5 Hz, 1H), 2.21−2.26 (m, 1H), 2.38−2.44 (m, 1H), 2.69 (dd, J=14, 7 Hz, 1H), 3.96 (s, 3H), 4.12−4.15 (m, 1H), 4.25 (s, 1H), 4.54−4.59 (m, 2H), 4.82 (dd, J=10, 2 Hz, 1H), 5.10 (d, J=17 Hz, 1H), 5.23−5.30 (m, 1H), 5.60 (m, 1H), 7.12 (dd, J=9, 2 Hz, 1H), 7.30 (s, 1H), 7.40 (d, J=2 Hz, lH), 7.51−7.58 (m, 3H), 7.74−7.81 (m, 2H), 7.87−7.91 (m, 1H), 8.04,8.05 (2s, 2H), 8.12 (d, J=9 Hz, 1H), 8.32 (d, J=7 Hz, 1H). Compound 48

LC / MS rt-min (MH ⁺ ): 1.74 (894) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.01 (s, 9H), 1.26, 1.28 (2s, 9H), 1.30 −1.33 (m, 1H), 1.72 (dd, J = 8,5 Hz, 1H), 2.21−2.26 (m, 1H), 2.38−2.44 (m, 1H), 2.69 (dd, J = 14, 7 Hz , 1H), 3.96 (s, 3H), 4.12−4.15 (m, 1H), 4.25 (s, 1H), 4.54−4.59 (m, 2H), 4.82 (dd, J = 10, 2 Hz, 1H), 5.10 (d, J = 17 Hz, 1H), 5.23-5.30 (m, 1H), 5.60 (m, 1H), 7.12 (dd, J = 9, 2 Hz, 1H), 7.30 (s, 1H), 7.40 (d, J = 2 Hz, lH), 7.51−7.58 (m, 3H), 7.74−7.81 (m, 2H), 7.87−7.91 (m, 1H), 8.04,8.05 (2s, 2H), 8.12 (d , J = 9 Hz, 1H), 8.32 (d, J = 7 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.67 (844) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) 8 1.04 (s, 9H), 1.26 (s, 9H), 1.43 (m, 1H), 1.68−1.70 (m, 1H), 1.92−2.00 (m, 1H), 2.57−2.65 (m, 1H), 2.74 (dd, J=14,8 Hz, 1H), 3.95 (s, 3H), 4.18−4.27 (m, 2H), 4.49−4.59 (m, 2H), 4.89−4.93 (m, 1H), 5.11 (dd, J=17, 2 Hz, 1H), 5.56 (m, 1H), 5.62−5.72 (m, 1H), 7.04−7.14 (m, 3H), 7.28 (s, 1H), 7.39−7.41 (m, 1H), 7.48−7.55 (m, 3H), 7.87−7.93 (m, 2H), 8.06−8.13 (m, 3H). Compound 49

LC / MS rt-min (MH ⁺ ): 1.67 (844) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) 8 1.04 (s, 9H), 1.26 (s, 9H), 1.43 (m , 1H), 1.68−1.70 (m, 1H), 1.92−2.00 (m, 1H), 2.57−2.65 (m, 1H), 2.74 (dd, J = 14,8 Hz, 1H), 3.95 (s, 3H ), 4.18−4.27 (m, 2H), 4.49−4.59 (m, 2H), 4.89−4.93 (m, 1H), 5.11 (dd, J = 17, 2 Hz, 1H), 5.56 (m, 1H), 5.62−5.72 (m, 1H), 7.04−7.14 (m, 3H), 7.28 (s, 1H), 7.39−7.41 (m, 1H), 7.48−7.55 (m, 3H), 7.87−7.93 (m, 2H ), 8.06−8.13 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.55 (851) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 0.76 (s, 9H), 1.35 (s, 9H), 1.49 (dd, J=9.5, 5.5 Hz, 1H), 2.03−2.05 (m, 1H), 2.31−2.43 (m, 2H), 2.71 (dd, J=13,6 Hz, 1H), 3.95 (s, 3H), 4.04−4.13 (m, 1H), 4.48−4.64 (m, 2H), 5.07−5.16 (m, 1H), 5.23−5.34 (m, 1H), 5.55−5.76 (m, 2H), 7.05−7.10 (m, 1H), 7.25 (s, 1H), 7.40 (d, J=2 Hz, 1H), 7.47−7.58 (m, 4H), 7.78−7.89 (m, 1H), 7.92−7.99 (m, 1H), 8.03, 8.05 (2s, 2H), 8.09−8.17 (m, 1H), 8.39 (d, J=7. 3 Hz, 1H). Compound 50

LC / MS rt-min (MH ⁺ ): 1.55 (851) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 0.76 (s, 9H), 1.35 (s, 9H), 1.49 (dd , J = 9.5, 5.5 Hz, 1H), 2.03−2.05 (m, 1H), 2.31−2.43 (m, 2H), 2.71 (dd, J = 13,6 Hz, 1H), 3.95 (s, 3H), 4.04−4.13 (m, 1H), 4.48−4.64 (m, 2H), 5.07−5.16 (m, 1H), 5.23−5.34 (m, 1H), 5.55−5.76 (m, 2H), 7.05−7.10 (m , 1H), 7.25 (s, 1H), 7.40 (d, J = 2 Hz, 1H), 7.47−7.58 (m, 4H), 7.78−7.89 (m, 1H), 7.92−7.99 (m, 1H), 8.03, 8.05 (2s, 2H), 8.09-8.17 (m, 1H), 8.39 (d, J = 7.3 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.66 (871) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.06 (s, 9H), 1.26 (s, 9H), 1.43 (m, 1H), 1.69−1.72 (m, 1H), 2.09−2.15 (m, 1H), 2.42−2.48 (m, 1H), 2.71 (dd, J=14, 7 Hz, 1H), 3.96 (s, 3H), 4.13−4.16 (m, 1H), 4.22−4.26 (m, 1H), 4.55−4.58 (m, 2H), 4.89 (d, J=10 Hz, 1H), 5.14 (d, J=17 Hz, 1H), 5.47−5. 54 (m, 1H), 5.62 (m, 1H), 6.63 (d, J=8. 8 Hz, 1H), 7.13−7.15 (m, 1H), 7.35 (s, 1H), 7.40 (s, 1H), 7.54−7.61 (m, 3H), 8.04, 8.06 (2s, 2H), 8.15 (d, J=9 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.44 (d, J=8 Hz, 1H), 8.72 (d, J=9 Hz, 1H). Compound 51

LC / MS rt-min (MH ⁺ ): 1.66 (871) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.06 (s, 9H), 1.26 (s, 9H), 1.43 (m , 1H), 1.69−1.72 (m, 1H), 2.09−2.15 (m, 1H), 2.42−2.48 (m, 1H), 2.71 (dd, J = 14, 7 Hz, 1H), 3.96 (s, 3H ), 4.13−4.16 (m, 1H), 4.22−4.26 (m, 1H), 4.55−4.58 (m, 2H), 4.89 (d, J = 10 Hz, 1H), 5.14 (d, J = 17 Hz, 1H), 5.47−5.54 (m, 1H), 5.62 (m, 1H), 6.63 (d, J = 8.8 Hz, 1H), 7.13−7.15 (m, 1H), 7.35 (s, 1H) , 7.40 (s, 1H), 7.54-7.61 (m, 3H), 8.04, 8.06 (2s, 2H), 8.15 (d, J = 9 Hz, 1H), 8.31 (d, J = 8 Hz, 1H), 8.44 (d, J = 8 Hz, 1H), 8.72 (d, J = 9 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.70 (871) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 500MHz) δ 1.05 (s, 9H), 1.26 (s, 9H), 1.27−1.31 (m, 1H), 1.70 (dd, J=8,5, Hz, 1H), 2.10−2.16 (m, 1H), 2.42−2.50 (m, 1H), 2.71 (dd, J=14, 7 Hz, 1H), 3.95 (s, 3H), 4.12−4.14 (m, 1H), 4.24 (s, 1H), 4.54−4.60 (m, 2H), 4.91 (d, J=12 Hz, 1H), 5.15 (d, J=17 Hz, 1H), 5.51−5.59 (m, 2H), 7.13 (dd, J=9, 2 Hz, 1H), 7.31 (s, 1H), 7.38 (d, J=2 Hz, 1H), 7.53−7.56 (m, 3H), 7.99−8.04 (m, 2H), 8.09−8.31 (m, 3H), 8.27 (d, J=9 Hz, 1H). Compound 52

LC / MS rt-min (MH ⁺ ): 1.70 (871) (Method A). ¹ H NMR: (Methanol-d ₄ , 500 MHz) δ 1.05 (s, 9H), 1.26 (s, 9H), 1.27-1.31 (m, 1H), 1.70 (dd, J = 8,5, Hz, 1H), 2.10−2.16 (m, 1H), 2.42−2.50 (m, 1H), 2.71 (dd, J = 14, 7 Hz, 1H), 3.95 (s, 3H), 4.12−4.14 (m, 1H), 4.24 (s, 1H), 4.54−4.60 (m, 2H), 4.91 (d, J = 12 Hz, 1H), 5.15 (d , J = 17 Hz, 1H), 5.51−5.59 (m, 2H), 7.13 (dd, J = 9, 2 Hz, 1H), 7.31 (s, 1H), 7.38 (d, J = 2 Hz, 1H) , 7.53−7.56 (m, 3H), 7.99−8.04 (m, 2H), 8.09−8.31 (m, 3H), 8.27 (d, J = 9 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.70 (871) (方法A). ¹Ｈ ＮＭＲ: (メタノール−d₄, 300MHz) δ 1.02 (s, 9H), 1.26 (s, 9H), 1.42 (m, 1H), 1.66−1.72 (m, 1H), 1.90−1.98 (m, 1H), 2.56−2.66 (m, 1H), 2.70−2.80 (m, 1H), 3.93 (s, 3H), 4.16−4.26 (m, 2H), 4.47−4.59 (m, 2H), 5.09 (dd, J=17, 1.5 Hz, 1H), 5.54 (m, 1H), 5.60−5.78 (m, 1H), 6.60 (d, J=8.8 Hz, 1H), 7.06 (dd, J=9,2 Hz, 1H), 7.26 (s, 1H), 7.37−7.40 (m, 1H), 7.48−7.65 (m, 4H), 8.04−8.10 (m, 3H), 8.18−8.29 (m, 2H), 8.67 (s, 1H). Compound 53

LC / MS rt-min (MH ⁺ ): 1.70 (871) (Method A). ¹ H NMR: (Methanol-d ₄ , 300 MHz) δ 1.02 (s, 9H), 1.26 (s, 9H), 1.42 (m , 1H), 1.66−1.72 (m, 1H), 1.90−1.98 (m, 1H), 2.56−2.66 (m, 1H), 2.70−2.80 (m, 1H), 3.93 (s, 3H), 4.16−4.26 (m, 2H), 4.47−4.59 (m, 2H), 5.09 (dd, J = 17, 1.5 Hz, 1H), 5.54 (m, 1H), 5.60−5.78 (m, 1H), 6.60 (d, J = 8.8 Hz, 1H), 7.06 (dd, J = 9,2 Hz, 1H), 7.26 (s, 1H), 7.37−7.40 (m, 1H), 7.48−7.65 (m, 4H), 8.04−8.10 ( m, 3H), 8.18-8.29 (m, 2H), 8.67 (s, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.79 (844) (方法B). ¹Ｈ ＮＭＲ: (メタノール−d₄, 300MHz) δ 1.02 (s, 9H), 1.25 (s, 9H), 1.43 (m, 1H), 1.77 (dd, J=8, 5 Hz, 1H), 2.00−2.19 (m, 1H), 2.38−2.69 (m, 2H), 3.91 (s, 3H), 4.03−4.14 (m, 1H), 4.20−4.33 (m, 1H), 4.45 (d, J=12 Hz, 1H), 4.55 (t, J=9 Hz, 1H), 5.12 (d, J=17 Hz, 1H), 5.44 (m, 1H), 5.67−5.88 (m, 1H), 7.01−7.18 (m, 4H), 7.34 (s, 1H), 7.40−7.57 (m, 3H), 7.82−7.92 (m, 1H), 8.01−8.10 (m, 3H). Compound 54

LC / MS rt-min (MH ⁺ ): 1.79 (844) (Method B). ¹ H NMR: (Methanol-d ₄ , 300 MHz) δ 1.02 (s, 9H), 1.25 (s, 9H), 1.43 (m , 1H), 1.77 (dd, J = 8, 5 Hz, 1H), 2.00−2.19 (m, 1H), 2.38−2.69 (m, 2H), 3.91 (s, 3H), 4.03−4.14 (m, 1H ), 4.20−4.33 (m, 1H), 4.45 (d, J = 12 Hz, 1H), 4.55 (t, J = 9 Hz, 1H), 5.12 (d, J = 17 Hz, 1H), 5.44 (m , 1H), 5.67−5.88 (m, 1H), 7.01−7.18 (m, 4H), 7.34 (s, 1H), 7.40−7.57 (m, 3H), 7.82−7.92 (m, 1H), 8.01−8.10 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.75 (905, MS) (方法A). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.02 (s, 9H), 1.25 (s, 9H), 1.42 (m, 1H), 1.75 (dd, J=8,5 Hz, 1H), 2.00−2.12 (m, 1H), 2.38−2.46 (m, 1H), 2.57−2.69 (m, 1H), 3.90 (s, 3H), 4.03−4.10 (m, 1H), 4.23 (s, 1H), 4.47 (d, J=12 Hz, 1H), 4.54 (t, J=9 Hz, 2H), 4.93 (d, J=ll Hz, 1H), 5.14 (d, J=17 Hz, 1H), 5.44 (m, 1H), 5.62−5.84 (m, 1H), 7.04 (dd, J=9, 2.6 Hz, 1H), 7.19 (s, 1H), 7.29−7.37 (m, 2H), 7.45−7.61 (m, 4H), 7.77−7.88 (m, 1H), 7.98−8.11 (m, 4H). Compound 55

LC / MS rt-min (MH ⁺ ): 1.75 (905, MS) (Method A). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.02 (s, 9H), 1.25 (s, 9H), 1.42 ( m, 1H), 1.75 (dd, J = 8,5 Hz, 1H), 2.00−2.12 (m, 1H), 2.38−2.46 (m, 1H), 2.57−2.69 (m, 1H), 3.90 (s, 3H), 4.03−4.10 (m, 1H), 4.23 (s, 1H), 4.47 (d, J = 12 Hz, 1H), 4.54 (t, J = 9 Hz, 2H), 4.93 (d, J = ll Hz, 1H), 5.14 (d, J = 17 Hz, 1H), 5.44 (m, 1H), 5.62−5.84 (m, 1H), 7.04 (dd, J = 9, 2.6 Hz, 1H), 7.19 (s , 1H), 7.29-7.37 (m, 2H), 7.45-7.61 (m, 4H), 7.77-7.88 (m, 1H), 7.98-8.11 (m, 4H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.72 (952, MS) (方法A). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz), δ 1.02 (s, 9H), 1.26 (s, 9H), 1.32 (m, 1H), 1.84 (dd, J=7. 5,5 Hz, 1H), 2.06−2.13 (m, 1H), 2.43−2.52 (m, 1H), 2.63 (dd, J=14,7 Hz 1H), 3.92 (s, 3H), 4.03−4.10 (m, 1H), 4.23 (s, 1H), 4.45 (d, J=11 Hz, 2H), 4.53−4.58 (m, 2H), 4.89 (m, 1H), 5.08−5.20 (m, 1H), 5.36, 5.42 (m, 1H), 5.71−5.99 (m, 1H), 7.02−7.08 (m, 2H), 7.16 (s, 1H), 7.31−7.38 (m, 2H), 7.44−7.53 (m, 3H), 7.90−8.13 (m, 5H). ＨＲＭＳ C₄₄H₅₁IN₅0₉S：計算値 952.2452 実測値 952.2476. Compound 56

LC / MS rt-min (MH ⁺ ): 1.72 (952, MS) (Method A). ¹ H NMR: methanol-d ₄ , 300 MHz), δ 1.02 (s, 9H), 1.26 (s, 9H), 1.32 (m, 1H), 1.84 (dd, J = 7, 5, 5 Hz, 1H), 2.06−2.13 (m, 1H), 2.43−2.52 (m, 1H), 2.63 (dd, J = 14,7 Hz 1H), 3.92 (s, 3H), 4.03−4.10 (m, 1H), 4.23 (s, 1H), 4.45 (d, J = 11 Hz, 2H), 4.53−4.58 (m, 2H), 4.89 (m , 1H), 5.08−5.20 (m, 1H), 5.36, 5.42 (m, 1H), 5.71−5.99 (m, 1H), 7.02−7.08 (m, 2H), 7.16 (s, 1H), 7.31−7.38 (m, 2H), 7.44-7.53 (m, 3H), 7.90-8.13 (m, 5H). HRMS C ₄₄ H ₅₁ IN ₅ 0 ₉ S: Calculated value 952.2452 Actual value 952.2476.

ＬＣ／ＭＳ rt−min (MH⁺): 1.64 (884) (方法A). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.04 (s, 9H), 1.23 (s, 9H), 1.28−1.37 (m, 1H), 1.72 (dd, J=7.9, 5.7 Hz, 1H), 2.11−2.20 (m, 1H), 2.45−2.54 (m, 1H), 2.78 (dd, J=13.4, 6.8 Hz, 1H), 3.95 (s, 3H), 4.03 (s, 3H), 4.10−4.19 (m, 1H), 4.25−4.35 (m, 1H), 4.64−4.73 (m, 2H), 5.04 (d, J=17.9 Hz, 1H), 5.16−5.28 (m, 1H), 5.80 (m, 1H), 7.30 (dd, J=9.2, 1.8. Hz, 1H), 7.50 (d, J=2.2 Hz, 1H), 7.56 (s, 1H), 7.60 (m, 6H), 8.06−8.08 (m, 2H), 8.15 (d, J=7.3 Hz, 1H), 8.30 (d, J=9.2 Hz, 1H). Compound 57

LC / MS rt-min (MH ⁺ ): 1.64 (884) (Method A). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.04 (s, 9H), 1.23 (s, 9H), 1.28-1.37 ( m, 1H), 1.72 (dd, J = 7.9, 5.7 Hz, 1H), 2.11−2.20 (m, 1H), 2.45−2.54 (m, 1H), 2.78 (dd, J = 13.4, 6.8 Hz, 1H) , 3.95 (s, 3H), 4.03 (s, 3H), 4.10−4.19 (m, 1H), 4.25−4.35 (m, 1H), 4.64−4.73 (m, 2H), 5.04 (d, J = 17.9 Hz , 1H), 5.16-5.28 (m, 1H), 5.80 (m, 1H), 7.30 (dd, J = 9.2, 1.8.Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.56 (s , 1H), 7.60 (m, 6H), 8.06-8.08 (m, 2H), 8.15 (d, J = 7.3 Hz, 1H), 8.30 (d, J = 9.2 Hz, 1H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.57 (884) (方法B). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.03 (s, 9H), 1.24, 1.29 (2s, 10H), 1.43 (s, 1H), 1.55−1.86 (m, 2H), 2.00 (m, 1H), 2.09 (s, 3H), 2.36−2.45 (m, 1H), 2.59−2.66 (m, 1H), 3.92, 3.94 (2s, 3H), 4.10 (m, 1H), 4.23−4.26 (m, 1H), 4.45−4.58 (m, 2H), 4.91 (d, J=11. 7 Hz, 1H), 5.12 (d, J=16.8 Hz, 1H), 5.44 (s, 1H), 5.64−5.76 (m, 1H), 7.05 (dd, J=9.2, 2.4 Hz, 1H), 7.20 (s, 1H), 7.36 (d, J=2.4 Hz, 2H), 7.47−7.55 (m, 3H), 7.59−7.64 (m, 2H), 7.79−7.84 (m, 2H), 8.02−8.08 (m, 3H). Compound 58

LC / MS rt-min (MH ⁺ ): 1.57 (884) (Method B). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.03 (s, 9H), 1.24, 1.29 (2s, 10H), 1.43 ( s, 1H), 1.55-1.86 (m, 2H), 2.00 (m, 1H), 2.09 (s, 3H), 2.36−2.45 (m, 1H), 2.59−2.66 (m, 1H), 3.92, 3.94 ( 2s, 3H), 4.10 (m, 1H), 4.23−4.26 (m, 1H), 4.45−4.58 (m, 2H), 4.91 (d, J = 11.7 Hz, 1H), 5.12 (d, J = 16.8 Hz, 1H), 5.44 (s, 1H), 5.64−5.76 (m, 1H), 7.05 (dd, J = 9.2, 2.4 Hz, 1H), 7.20 (s, 1H), 7.36 (d, J = 2.4 Hz, 2H), 7.47−7.55 (m, 3H), 7.59−7.64 (m, 2H), 7.79−7.84 (m, 2H), 8.02−8.08 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.74 (857) (方法B). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.05 (s, 9H), 1.26 (s, 9H), 1.43 (m, 1H), 1.70−1.79, (m, 1H), 2.10 (q, J=8.8 Hz, 1H), 2.32−2.41 (m, 1H), 2.62 (dd, J=13,7 Hz, 1H), 3.79 (s, 3H), 3.93 (s, 3H), 4.06−4.11 (m, 1H), 4.24−4.33 (m, 1H), 4.48−4.57 (m, 2H), 5.00 (d, J=12.1 Hz, 1H), 5.14 (d, J=17.2 Hz, 1H), 5.48 (m, 1H), 5.64−5.66 (m, 1H), 6.91−6.96 (m, 1H), 7.01−7.07 (m, 1H), 7.18−7.41 (m, 3H), 7.47−7.55 (m, 3H), 7.80−7.78 (m, 2H), 8.02−8.08 (m, 3H). Compound 59

LC / MS rt-min (MH ⁺ ): 1.74 (857) (Method B). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.05 (s, 9H), 1.26 (s, 9H), 1.43 (m, 1H), 1.70−1.79, (m, 1H), 2.10 (q, J = 8.8 Hz, 1H), 2.32−2.41 (m, 1H), 2.62 (dd, J = 13,7 Hz, 1H), 3.79 ( s, 3H), 3.93 (s, 3H), 4.06−4.11 (m, 1H), 4.24−4.33 (m, 1H), 4.48−4.57 (m, 2H), 5.00 (d, J = 12.1 Hz, 1H) , 5.14 (d, J = 17.2 Hz, 1H), 5.48 (m, 1H), 5.64−5.66 (m, 1H), 6.91−6.96 (m, 1H), 7.01−7.07 (m, 1H), 7.18−7.41 (m, 3H), 7.47-7.55 (m, 3H), 7.80-7.78 (m, 2H), 8.02-8.08 (m, 3H).

¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.04 (s, 9H), 1.24−1.44 (m, 19H), 1.76 (dd, J=8,5 Hz, 1H), 2.03−2.21 (m, 1H), 2.40−2.50 (m, 1H), 2.58−2.65 (m, 1H), 3.93 (s, 3H), 4.08−4.14 (m, 1H), 4.24 (s, 1H), 4.45−4.58 (m, 2H), 4.92 (dd, J=10.4, 2 Hz, 1H), 5.15 (d, J=17.2 Hz, 1H), 5.47 (m, 1H), 5.71 (m, 1H), 7.05 (dd, J=9,2 Hz, 1H), 7.20 (s, 1H), 7.34−7.68 (m, 6H), 7.77−7.83 (m, 2H), 7.95−8.07 (m, 3H). Compound 60

¹ H NMR: Methanol-d ₄ , 300 MHz) δ 1.04 (s, 9H), 1.24−1.44 (m, 19H), 1.76 (dd, J = 8,5 Hz, 1H), 2.03−2.21 (m, 1H) , 2.40−2.50 (m, 1H), 2.58−2.65 (m, 1H), 3.93 (s, 3H), 4.08−4.14 (m, 1H), 4.24 (s, 1H), 4.45−4.58 (m, 2H) , 4.92 (dd, J = 10.4, 2 Hz, 1H), 5.15 (d, J = 17.2 Hz, 1H), 5.47 (m, 1H), 5.71 (m, 1H), 7.05 (dd, J = 9,2 Hz, 1H), 7.20 (s, 1H), 7.34−7.68 (m, 6H), 7.77−7.83 (m, 2H), 7.95−8.07 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.58 (790) (方法A) ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.05 (s, 9H), 1.26, 1.27 (2s, 18H), 1.33−1.44 (m, 1H), 1.81−1.85 (m, 1H), 2.18−2.35 (m, 2H), 2.67−2.74 (m, 1H), 3.95 (s, 3H), 4.01−4.10 (m, 1H), 4.19−4.25 (m, 1H), 4.57−4.62 (m, 2H), 5.10 (d, J=12 Hz, 1H), 5.24 (d, J=17 Hz, 1H), 5.53−5.65 (m, 2H), 6.51 (d, J=9 Hz, 1H), 7.07 (dd, J=9, 2 Hz, 1H), 7.25 (s, 1H), 7.40 (d, J=2 Hz, 1H), 7.47−7.57 (m, 3H), 8.03−8.06 (m, 2H), 8.10 (d, J=9 Hz, 1H) ; ＨＲＭＳ m/z (M+H)⁺ C₄₂H₅₆N₅SO₈: 計算値 790.3850 実測値: 790.3834. Compound 61

LC / MS rt-min (MH ⁺ ): 1.58 (790) (Method A) ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.05 (s, 9H), 1.26, 1.27 (2s, 18H), 1.33-1.44 (m, 1H), 1.81-1.85 (m, 1H), 2.18-2.35 (m, 2H), 2.67-2.74 (m, 1H), 3.95 (s, 3H), 4.01-4.10 (m, 1H), 4.19 −4.25 (m, 1H), 4.57−4.62 (m, 2H), 5.10 (d, J = 12 Hz, 1H), 5.24 (d, J = 17 Hz, 1H), 5.53−5.65 (m, 2H), 6.51 (d, J = 9 Hz, 1H), 7.07 (dd, J = 9, 2 Hz, 1H), 7.25 (s, 1H), 7.40 (d, J = 2 Hz, 1H), 7.47−7.57 (m , 3H), 8.03−8.06 (m, 2H), 8.10 (d, J = 9 Hz, 1H); HRMS m / z (M + H) ⁺ C ₄₂ H ₅₆ N ₅ SO ₈ : Calculated value 790.3850 Actual value: 790.3834.

ＬＣ／ＭＳ rt−min (MH⁺): 1.61 (790) (方法A). ¹Ｈ ＮＭＲ:メタノール−d₄, 300MHz) δ 1.03 (s, 9H), 1.21−1.37 (m, 1H), 1.23 (s, 9H), 1.29 (s, 9H), 1.79−1.86 (m, 1H), 2.00−2.39 (m, 1H), 2.68−2.72 (m, 1H), 3.95 (s, 3H), 4.04−4.13 (m, 1H), 4.24−4.33 (m, 1H), 4.54−4.69 (m, 2H), 5.09 (d, J=10 Hz, 1H), 5.28 (d, J=17 Hz, 1H), 5.48−5.67 (m, 2H), 7.05−7.09 (m, 1H), 7.26 (s, 1H), 7.40 (m, 1H), 7.49−7.62 (m, 3H), 8.04−8.11 (m, 3H); ＨＲＭＳ m/z (M+H)⁺ C₄₂H₅₆N₅SO₈ 計算値: 790.3850 実測値: 790.3827. Compound 62

LC / MS rt-min (MH ⁺ ): 1.61 (790) (Method A). ¹ H NMR: Methanol-d ₄ , 300 MHz) δ 1.03 (s, 9H), 1.21-1.37 (m, 1H), 1.23 ( s, 9H), 1.29 (s, 9H), 1.79−1.86 (m, 1H), 2.00−2.39 (m, 1H), 2.68−2.72 (m, 1H), 3.95 (s, 3H), 4.04−4.13 ( m, 1H), 4.24−4.33 (m, 1H), 4.54−4.69 (m, 2H), 5.09 (d, J = 10 Hz, 1H), 5.28 (d, J = 17 Hz, 1H), 5.48−5.67 (m, 2H), 7.05−7.09 (m, 1H), 7.26 (s, 1H), 7.40 (m, 1H), 7.49−7.62 (m, 3H), 8.04−8.11 (m, 3H); HRMS m / z (M + H) ⁺ C ₄₂ H ₅₆ N ₅ SO ₈ Calculated value: 790.3850 Actual value: 790.3827.

ＬＣ／ＭＳ rt−min (MH⁺): 1.78 (841) (方法D) Compound 63

LC / MS rt−min (MH ⁺ ): 1.78 (841) (Method D)

ＬＣ／ＭＳ rt−min (MH⁺): 2.04 (953, MS) (方法B). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.06, 1.08 (2s, 9H), 1.20−1.29 (m, 28H), 1.43 (m, 1H), 1.73 (dd, J=7.9, 5.7 Hz 1H), 2.03−2.14 (m, 1H), 2.38 (m, 1H), 2.68 (dd, J=13.9, 6.2 Hz, 1H), 2.85−2. 94 (m, 1H), 3.95 (s, 3H), 4.14 (dd, J=11.9, 2.7 Hz, 1H), 4.24−4.36 (m, 3H), 4.48−4.61 (m, 2H), 4.78 (d, J=11. 3 Hz, 1H), 5.06 (d, J=17.2 Hz, 1H), 5.58 (m, 1H), 7.07−7.11 (m, 1H), 7.18 (s, 2H), 7.27 (s, 1H), 7.40 (d, J=1. 8, 1H), 7.47−7.57 (m, 3H), 8.04−8.11 (m, 3H). ＨＲＭＳ C₅₃H₇₀N₅0₉S 計算値 952.4894 実測値 952.4898. Compound 64

LC / MS rt-min (MH ⁺ ): 2.04 (953, MS) (Method B). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.06, 1.08 (2s, 9H), 1.20-1.29 (m, 28H ), 1.43 (m, 1H), 1.73 (dd, J = 7.9, 5.7 Hz 1H), 2.03−2.14 (m, 1H), 2.38 (m, 1H), 2.68 (dd, J = 13.9, 6.2 Hz, 1H ), 2.85−2.94 (m, 1H), 3.95 (s, 3H), 4.14 (dd, J = 11.9, 2.7 Hz, 1H), 4.24−4.36 (m, 3H), 4.48−4.61 (m, 2H) ), 4.78 (d, J = 11.3 Hz, 1H), 5.06 (d, J = 17.2 Hz, 1H), 5.58 (m, 1H), 7.07−7.11 (m, 1H), 7.18 (s, 2H) , 7.27 (s, 1H), 7.40 (d, J = 1.8, 1H), 7.47−7.57 (m, 3H), 8.04−8.11 (m, 3H). HRMS C ₅₃ H ₇₀ N ₅ 0 ₉ S Calculation Value 952.4894 Actual value 952.4898.

ＬＣ／ＭＳ rt−min (MH⁺): 1.77 (902) (方法B). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.04 (s, 9H), 1.27 (s, 9H), 1.43 (m, 1H), 1.74 (m, 1H), 2.06 (m, 1H), 2.33−2.71 (m, 2H), 3.94 (s, 3H), 4.09 (m, 1H), 4.24 (m, 1H), 4.42−4.58 (m, 2H), 4.91−4.94 (m, 1H), 5.15 (d, J=16.5 Hz, 1H), 5.47 (m, 1H), 5.74 (m, 1H), 7.04−7.07 (m, 1H), 7.34−7.68 (m, 12H), 7.94−8.07 (m, 5H). ＨＲＭＳ C₅₀H₅₆N₅O₉S 計算値 902.3799 実測値 902.3790. Compound 65

LC / MS rt-min (MH ⁺ ): 1.77 (902) (Method B). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.04 (s, 9H), 1.27 (s, 9H), 1.43 (m, 1H), 1.74 (m, 1H), 2.06 (m, 1H), 2.33-2.71 (m, 2H), 3.94 (s, 3H), 4.09 (m, 1H), 4.24 (m, 1H), 4.42−4.58 (m, 2H), 4.91−4.94 (m, 1H), 5.15 (d, J = 16.5 Hz, 1H), 5.47 (m, 1H), 5.74 (m, 1H), 7.04−7.07 (m, 1H), 7.34−7.68 (m, 12H), 7.94−8.07 (m, 5H). HRMS C ₅₀ H ₅₆ N ₅ O ₉ S Calculated value 902.3799 Actual value 902.3790.

ＬＣ／ＭＳ rt−min (MH⁺): 1.86 (909) (方法B) ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.03 (s, 9H), 1.25, 1.30 (2s, 9H), 1.43 (m, 1H), 1.72−1. 76 (m, 1H), 2.02−2.11 (m, 1H), 2.42−2.51 (m, 1H), 2.61−2.71 (m, 1H), 3.93, 3.94 (2s, 3H), 4.08−4.13 (m, 1H), 4.23 (s, 1H), 4.47−4.58 (m, 2H), 5.12 (d, J=17. 2 Hz, 1H), 5.50 (m, 1H), 5.64−5.78 (m, 1H), 7.06 (dd, J=9.2, 2.6 Hz, 1H), 7.23 (s, 1H), 7.28−7.32 (m, 2H), 7.37−7.39 (m, 1H), 7.47−7.55 (m, 3H), 7.89−8.12 (m, 5H). ＨＲＭＳ C₄₅H₅₁F₃N₅O₁₀S 計算値 910.3309 実測値 910.3298. Compound 66

LC / MS rt-min (MH ⁺ ): 1.86 (909) (Method B) ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.03 (s, 9H), 1.25, 1.30 (2s, 9H), 1.43 (m , 1H), 1.72-1.76 (m, 1H), 2.02−2.11 (m, 1H), 2.42−2.51 (m, 1H), 2.61−2.71 (m, 1H), 3.93, 3.94 (2s, 3H) , 4.08−4.13 (m, 1H), 4.23 (s, 1H), 4.47−4.58 (m, 2H), 5.12 (d, J = 17.2 Hz, 1H), 5.50 (m, 1H), 5.64−5.78 (m, 1H), 7.06 (dd, J = 9.2, 2.6 Hz, 1H), 7.23 (s, 1H), 7.28-7.32 (m, 2H), 7.37-7.39 (m, 1H), 7.47-7.55 (m , 3H), 7.89-8.12 (m, 5H). HRMS C ₄₅ H ₅₁ F ₃ N ₅ O ₁₀ S calculated 910.3309 measured 910.3298

ＬＣ／ＭＳ rt−min (MH⁺): 1.43 (764) (方法A). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.03 (s, 9H), 1.26 (s, 9H), 1.44−1.52 (m, 1H), 1.52−1.65 (m, 11H), 2.27−2.37 (m, 1H), 2.65 (dd, J=13.7, 6.8 Hz, 1H), 2.92−3.01 (m, 1H), 3.94 (s, 3H), 4.07−4.13 (m, 1H), 4.26 (d, J=9.2 Hz, 1H), 4.48−4.53 (m, 1H), 5.56 (s, 1H), 6.67 (d, J=9.5 Hz, NH), 7.24 (s, 1H), 7.36−7.38 (m, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.47−7.57 (m, 3H), 8.03−8.07 (m, 3H). Compound 67

LC / MS rt-min (MH ⁺ ): 1.43 (764) (Method A). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.03 (s, 9H), 1.26 (s, 9H), 1.44-1.52 ( m, 1H), 1.52-1.65 (m, 11H), 2.27-2.37 (m, 1H), 2.65 (dd, J = 13.7, 6.8 Hz, 1H), 2.92-3.01 (m, 1H), 3.94 (s, 3H), 4.07−4.13 (m, 1H), 4.26 (d, J = 9.2 Hz, 1H), 4.48−4.53 (m, 1H), 5.56 (s, 1H), 6.67 (d, J = 9.5 Hz, NH ), 7.24 (s, 1H), 7.36−7.38 (m, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.47−7.57 (m, 3H), 8.03−8.07 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.49 (764) (方法A). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 0.86−1.16 (m, 6H), 1.19 (s, 9H), 1. 43−1. 91 (m, 3H), 2.33−2.42 (m, 1H), 2.51−2.68 (m, 2H), 2.92−3.03 (m, 1H), 3.95 (s, 3H), 4.05−4.12 (m, 2H), 4.54 (dd, J=10.6, 6.2 Hz, 1H), 4.67 (d, J=12.1 Hz, 1H), 5.58 (s, 1H), 6.78 (d, J=9.5 Hz, NH), 7.09 (dd, J=9.2, 2.4 Hz, 1H), 7.25 (s, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.47−7.57 (m, 3H), 8.03−8.10 (m, 3H). Compound 68

LC / MS rt-min (MH ⁺ ): 1.49 (764) (Method A). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 0.86-1.16 (m, 6H), 1.19 (s, 9H), 1. 43−1.91 (m, 3H), 2.33−2.42 (m, 1H), 2.51−2.68 (m, 2H), 2.92−3.03 (m, 1H), 3.95 (s, 3H), 4.05−4.12 (m , 2H), 4.54 (dd, J = 10.6, 6.2 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 5.58 (s, 1H), 6.78 (d, J = 9.5 Hz, NH), 7.09 (dd, J = 9.2, 2.4 Hz, 1H), 7.25 (s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.47−7.57 (m, 3H), 8.03−8.10 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.49 (788) (方法B). ¹Ｈ ＮＭＲ:メタノール−d₄, 300MHz) δ 0.85−1.75 (m, 13H), 1.47 (s, 9H), 1.75−1.80 (m, 1H), 1.95−2.04 (m, 1H), 2.47−3.03 (m, 3H), 3.93 (s, 3H), 4.0 (m, 2H), 4.51−4.69 (m, 2H), 4.93−5.02 (m, 1H), 5.31−5.40 (m, 1H), 5.46, 5.55 (2s, 1H), 5.80−5.94 (m, 1H), 7.12 (dd, J=9.2, 2.2 Hz, 1H), 7.18 (s, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.46−7.57 (m , 3H), 7.95 (d, J=9. 2 Hz, 1H), 8.04−8.11 (m, 2H) ; ＨＲＭＳ m/z (M+H)⁺ C₄₁H₅₀N₅SO₉: 計算値 788.3329, 実測値 788.3322. Compound 69
High Rf isomer (MeOH / CH ₂ Cl ₂ )

LC / MS rt-min (MH ⁺ ): 1.49 (788) (Method B). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 0.85-1.75 (m, 13H), 1.47 (s, 9H), 1.75- 1.80 (m, 1H), 1.95−2.04 (m, 1H), 2.47−3.03 (m, 3H), 3.93 (s, 3H), 4.0 (m, 2H), 4.51−4.69 (m, 2H), 4.93− 5.02 (m, 1H), 5.31−5.40 (m, 1H), 5.46, 5.55 (2s, 1H), 5.80−5.94 (m, 1H), 7.12 (dd, J = 9.2, 2.2 Hz, 1H), 7.18 ( s, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.46−7.57 (m, 3H), 7.95 (d, J = 9.2 Hz, 1H), 8.04−8.11 (m, 2H); HRMS m / z (M + H) ⁺ C ₄₁ H ₅₀ N ₅ SO ₉ : Calculated value 788.3329, Actual value 788.3322.

ＬＣ／ＭＳ rt−min (MH⁺): 1.55 (788) (方法B). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 0.98 (t, J=7.3 Hz, 3H), 1.09 (s, 9H), 1.26−1.93 (m, 10H), 2.12−2.21 (m, 1H), 2.32−2.40 (m, 1H), 2.53−2.65 (m, 1H), 2.80 (brs, 1H), 3.95 (s, 3H), 4.09−4.18 (m, 1H), 4.37 (d, J=12 Hz, 1H), 4.54−4.59 (m, 2H), 5.19 (d, J=9. 2 Hz, 1H), 5.33 (d, J=16. 5 Hz, 1H), 5.46−5.60 (m, 2H), 7.11−7.15 (m, 1H), 7.22 (s, 1H), 7.43 (d, J=2 Hz, 1H), 7.48−7.58 (m, 3H), 8.01−8.07 (m, 3H). ＨＲＭＳ m/z (M+H)⁺ C₄₁H₅₀N₅SO₉: 計算値 788.3329, 実測値 788.3330. Compound 70
Low Rf isomer (MeOH / CH ₂ Cl ₂ )

LC / MS rt-min (MH ⁺ ): 1.55 (788) (Method B). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 0.98 (t, J = 7.3 Hz, 3H), 1.09 (s, 9H) , 1.26−1.93 (m, 10H), 2.12−2.21 (m, 1H), 2.32−2.40 (m, 1H), 2.53−2.65 (m, 1H), 2.80 (brs, 1H), 3.95 (s, 3H) , 4.09−4.18 (m, 1H), 4.37 (d, J = 12 Hz, 1H), 4.54−4.59 (m, 2H), 5.19 (d, J = 9.2 Hz, 1H), 5.33 (d, J = 16.5 Hz, 1H), 5.46−5.60 (m, 2H), 7.11−7.15 (m, 1H), 7.22 (s, 1H), 7.43 (d, J = 2 Hz, 1H), 7.48−7.58 ( m, 3H), 8.01−8.07 (m, 3H). HRMS m / z (M + H) ⁺ C ₄₁ H ₅₀ N ₅ SO ₉ : Calculated value 788.3329, Actual value 788.3330.

ＬＣ／ＭＳ rt−min (MH⁺): 1.53 (790) (方法A). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 0.94 (d, J=6. 2 Hz, 6H), 1.08 (s, 9H), 1.28−1.33 (m, 1H), 1.70−2.74 (m, 10H), 3.68 (m, 1H), 3.93, 3.98 (2s, 3H), 4.04−4.33 (m, 2H), 4.45−4.60 (m, 2H), 5.14 (d, J=17.6 Hz, 1H), 5.53 (s, 1H), 5.78−5.90 (m, 1H), 7.20, 7.25 (2s, 1H), 7.37−7.42 (m, 1H), 7.49−7.56 (m, 4H), 8.03−8.06 (m, 3H). Compound 71

LC / MS rt-min (MH ⁺ ): 1.53 (790) (Method A). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 0.94 (d, J = 6.2 Hz, 6H), 1.08 (s, 9H), 1.28−1.33 (m, 1H), 1.70−2.74 (m, 10H), 3.68 (m, 1H), 3.93, 3.98 (2s, 3H), 4.04−4.33 (m, 2H), 4.45−4.60 ( m, 2H), 5.14 (d, J = 17.6 Hz, 1H), 5.53 (s, 1H), 5.78−5.90 (m, 1H), 7.20, 7.25 (2s, 1H), 7.37−7.42 (m, 1H) , 7.49-7.56 (m, 4H), 8.03-8.06 (m, 3H).

ＬＣ／ＭＳ rt−min (MH⁺): 1.62 (816). ¹Ｈ ＮＭＲ: メタノール−d₄, 300MHz) δ 1.24 (s, 9H), 1.39−1.58 (m, 2H), 1.50−2.53 (m, 17H), 2.72−2.80 (m, 1H), 3.75−3.89 (m, 1H), 3.94 (s, 3H), 4.02−4.13 (m, 2H), 4.54−4.67 (m, 2H), 5.03 (d, J=10.2 Hz, 1H), 5.24 (d, J=17.2 Hz, 1H), 5.54 (s, 1H), 5.78−5.93 (m, 1H), 7.08 (dd, J=9.2, 2 Hz, 1H), 7.25, 7.27 (2s, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.46−7.57 (m, 3H), 8.04−8.06 (m, 2H), 8.13 (d, J=9.2 Hz, 1H). Compound 72

LC / MS rt-min (MH ⁺ ): 1.62 (816). ¹ H NMR: methanol-d ₄ , 300 MHz) δ 1.24 (s, 9H), 1.39-1.58 (m, 2H), 1.50-2.53 (m, 17H), 2.72−2.80 (m, 1H), 3.75−3.89 (m, 1H), 3.94 (s, 3H), 4.02−4.13 (m, 2H), 4.54−4.67 (m, 2H), 5.03 (d, J = 10.2 Hz, 1H), 5.24 (d, J = 17.2 Hz, 1H), 5.54 (s, 1H), 5.78−5.93 (m, 1H), 7.08 (dd, J = 9.2, 2 Hz, 1H), 7.25, 7.27 (2s, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.46−7.57 (m, 3H), 8.04−8.06 (m, 2H), 8.13 (d, J = 9.2 Hz, 1H) .

ＬＣ／ＭＳ rt−min (MH⁺): 1.65 (883) (方法A). ¹Ｈ ＮＭＲ: メタノール−d₄, 500MHz) δ 0.22−0.27 (m, 2H), 0.50−0.56 (m, 2H), 0.86−1.36 (m, 5H), 1.09 (s, 9H), 1.46−1.48 (m, 1H), 1.90 (dd, J=8, 5 Hz, 1H), 2.18−2.24 (m, 1H), 2.30−2.46 (m, 1H), 2.70 (dd, J=14, 7 Hz, 1H), 3.07 (dd, J=15, 7 Hz, 1H), 3.13 (dd, J=15, 7 Hz, 1H), 3.43−3.49 (m, 2H), 3.98 (s, 3H), 4.16 (dd, J=12, 3 Hz, 1H), 4.50−4.54 (m, 2H), 4.57−4.61 (m, 1H), 5.12 (d, J=12 , Hz, 1H), 5.30 (d, J=17 Hz, 1H), 5.63 (m, 1H), 5.75 (d, J=9 Hz, NH), 5.83−5.90 (m, 1H), 7.13 (dd, J=9, 2 Hz, 1H), 7.31 (s, 1H), 7.43 (d, J=2 Hz, 1H), 7.52−7.59 (m, 3H), 8.08−8.10 (m, 3H). Compound 73

LC / MS rt-min (MH ⁺ ): 1.65 (883) (Method A). ¹ H NMR: methanol-d ₄ , 500 MHz) δ 0.22−0.27 (m, 2H), 0.50−0.56 (m, 2H), 0.86−1.36 (m, 5H), 1.09 (s, 9H), 1.46−1.48 (m, 1H), 1.90 (dd, J = 8, 5 Hz, 1H), 2.18−2.24 (m, 1H), 2.30− 2.46 (m, 1H), 2.70 (dd, J = 14, 7 Hz, 1H), 3.07 (dd, J = 15, 7 Hz, 1H), 3.13 (dd, J = 15, 7 Hz, 1H), 3.43 −3.49 (m, 2H), 3.98 (s, 3H), 4.16 (dd, J = 12, 3 Hz, 1H), 4.50−4.54 (m, 2H), 4.57−4.61 (m, 1H), 5.12 (d , J = 12, Hz, 1H), 5.30 (d, J = 17 Hz, 1H), 5.63 (m, 1H), 5.75 (d, J = 9 Hz, NH), 5.83−5.90 (m, 1H), 7.13 (dd, J = 9, 2 Hz, 1H), 7.31 (s, 1H), 7.43 (d, J = 2 Hz, 1H), 7.52-7.59 (m, 3H), 8.08-8.10 (m, 3H) .

化合物7４−(1S,2S)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.71 (806).
化合物７５−(1R,2R)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.69 (806). Compounds 74 and 75

Compound 744- (1S, 2S) isomer: LC / MS rt-min (MH ^<+> ): 1.71 (806).
Compound 75- (1R, 2R) isomer: LC / MS rt-min (MH ^<+> ): 1.69 (806).

(1R,2S／lS,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.69 (804). Compound 76

(1R, 2S / lS, 2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1.69 (804).

化合物７７−(lS,2S)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 2.10 (832).
化合物７８−(1R,2R)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.73 (832). Compounds 77 and 78

Compound 77- (lS, 2S) isomer: LC / MS rt-min (MH ^<+> ): 2.10 (832).
Compound 78- (1R, 2R) isomer: LC / MS rt-min (MH ^<+> ): 1.73 (832).

(1R,2S／1S,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.72 (830). Compound 79

(1R, 2S / 1S, 2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1.72 (830).

(1R,2R)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.87 (861). Compound 80

(1R, 2R) isomer: LC / MS rt-min (MH ⁺ ): 1.87 (861).

化合物８１−(1R,2S／1S,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.86 (858).
化合物８２−(lS,2R)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.87 (858).
化合物８３−(lR,2S)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.87 (858). Compound 81-83

Compound 81- (1R, 2S / 1S, 2R 1: 1 mixture): LC / MS rt-min (MH ^<+> ): 1.86 (858).
Compound 82- (lS, 2R) isomer: LC / MS rt-min (MH ^<+> ): 1.87 (858).
Compound 83- (lR, 2S) isomer: LC / MS rt-min (MH ^<+> ): 1.87 (858).

(1R,2S)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.66 (818). Compound 84

(1R, 2S) isomer: LC / MS rt-min (MH ⁺ ): 1.66 (818).

(1R,2S)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.57 (804). Compound 85

(1R, 2S) isomer: LC / MS rt-min (MH ⁺ ): 1.57 (804).

化合物８６−(1R,2S／lS,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.51 (764).
化合物８７−(1R,2S)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.50 (764).
化合物８８−(1S,2R)異性体: ＬＣ／ＭＳ rt−min (MH⁺): 1.52 (764). Compounds 86-88

Compound 86- (1R, 2 S / lS , 2R 1: 1 mixture): LC / MS rt-min (MH +): 1.51 (764).
Compound 87- (1R, 2S) isomer: LC / MS rt-min (MH ⁺ ): 1.50 (764).
Compound 88- (1 S , 2R) isomer: LC / MS rt-min (MH ⁺ ): 1.52 (764).

(1R,2S／1S,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.44 (750). Compound 89

(1R, 2S / 1S, 2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1.44 (750).

(1R,2S／1S,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1. 54 (764). Compound 90

(1R, 2S / 1S, 2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1. 54 (764).

(1R,25／15,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.52 (790). Compound 91

(1R, 25 / 15,2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1.52 (790).

(1R,2S／1S,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.45 (776). Compound 92

(1R, 2S / 1S, 2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1.45 (776).

(1R,2S／1S,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.55 (790). Compound 93

(1R, 2S / 1S, 2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1.55 (790).

(1R,2S／1S,2R １：１混合物): ＬＣ／ＭＳ rt−min (MH⁺): 1.65 (818). Compound 94

(1R, 2S / 1S, 2R 1: 1 mixture): LC / MS rt-min (MH ⁺ ): 1.65 (818).

Example 27
Compound 95, 1- {2- [bis- (2-hydroxy-ethyl) -amino] -acetyl} -4 (R)-(7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2 ( S) -carboxylic acid (1 (R) -cyclopropanesulfonylamino-carbonyl-2 (S) -vinyl-cyclopropyl) amide (below) was prepared as described in steps 27a-e below.

工程１２a(7.5 g, 39.1 mmol)の生成物を、ジクロロメタン(150 mL)中ジイソプロピルエチルアミン(32.5 mL, 186 mmol)と一緒にした。得られた混合物に、ＨＯＢＴ水和物(6.85 g, 44.7 mmol)および工程１cの生成物(17.3 g, 37.3 mmol)、ついで、ＨＢＴＵ(16.96 g, 44.7 mmol)を添加した。直後、わずかに発熱し、混合物を室温にて一夜攪拌した。ついで、混合物を真空にて濃縮し、酢酸エチル(600 mL)に再溶解させた。溶液を水(2 x 200 mL)で、ついで、10% 水性炭酸水素ナトリウム(2 x 200 mL)、ついで、水(150 mL)および最後に食塩水(150 mL)で洗滌した。有機層を無水硫酸マグネシウムで乾燥させ、ろ過し、ろ液を真空にてベージュ色のガラス状固体に濃縮した。精製は、Biotage Flash 75Mカートリッジ(66% ヘキサン／酢酸エチル)上フラッシュクロマトグラフィーで、複数のバッチ(各7 g)で行い、最初の溶出異性体として、Ｂoc−ＮＨ−Ｐ2−Ｐ1−ＣＯＯＥtの(1R,2S)ビニルＡcca Ｐ1異性体(9.86 g total, 44.0%収率)、ついで、第２の溶出異性体として、Ｂoc−ＮＨ−Ｐ2−Ｐl−ＣＯＯＥtの(1S,2R)ビニルＡccaＰ1異性体(10.43 g 全工程46.5%収率)を得た。合計1.97 gの画分混合物を回収し、２個のジアステレオマーへの変換全工程収率９９.３％を得た。 Step 27a: 2 (S)-(1 (R) -ethoxycarbonyl-2 (S) -vinyl-cyclopropylcarbamoyl) -4 (R)-(7-methoxy-2-phenyl-quinolin-4-yloxy)- Production of pyrrolidine-1-carboxylic acid tert-butyl ester (below)

The product of step 12a (7.5 g, 39.1 mmol) was combined with diisopropylethylamine (32.5 mL, 186 mmol) in dichloromethane (150 mL). To the resulting mixture was added HOBT hydrate (6.85 g, 44.7 mmol) and the product of step 1c (17.3 g, 37.3 mmol), followed by HBTU (16.96 g, 44.7 mmol). Immediately thereafter, a slight exotherm occurred and the mixture was stirred overnight at room temperature. The mixture was then concentrated in vacuo and redissolved in ethyl acetate (600 mL). The solution was washed with water (2 × 200 mL), then 10% aqueous sodium bicarbonate (2 × 200 mL), then water (150 mL) and finally with brine (150 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to a beige glassy solid. Purification was performed by flash chromatography on a Biotage Flash 75M cartridge (66% hexane / ethyl acetate) in multiple batches (7 g each) with the first eluting isomer as Boc-NH-P2-P1-COOEt ( 1R, 2S) Vinyl Acca P1 isomer (9.86 g total, 44.0% yield), and then, as the second eluting isomer, 10.43 g (46.5% yield in all steps) was obtained. A total of 1.97 g of fraction mixture was collected to give 99.3% overall process yield of conversion to two diastereomers.

(1R, 2S) isomer- ¹ H NMR: (methanol-d ₄ ) δ 1.23 (t, J = 7.2 Hz, 3H), 1.4 (s, 4H), 1.45 (s, 6H), 1.73 (dd, J = 7.9, 1.5 Hz, 0.4H), 1.79 (dd, J = 7.8, 2.4 Hz, 0.6H), 2.21 (q, J = 8.2 Hz, 1H), 2.44−2.49 (m, 1H), 2.66−2.72 ( m, 0.4H), 2.73−2.78 (m, 0.6H), 3.93−3.95 (m, 2H), 3.96 (s, 3H), 4.10−4.17 (m, 2H), 4.44 (q, J = 7.8 Hz, 1H), 5.13 (d, J = 10.7 Hz, 1H), 5.31 (d, J = 17.7 Hz, 0.4H), 5.32 (d, J = 17.4 Hz, 0.6H), 5.49 (bs, 1H), 5.66− 5.82 (m, 1H), 7.16 (dd, J = 9.2, 2.5 Hz, 1H), 7.26 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.48−7.55 (m, 3H), 8.02 −8.05 (m, 3H); LC-MS (HPLC condition “B”, retention time: 1.55), MS m / z 602 (M ⁺ +1).

Step 27b: 2 (S)-(1 (R) -carboxy-2 (S) -vinyl-cyclopropylcarbamoyl) -4 (R)-(7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine- Production of 1-carboxylic acid tert-butyl ester (below)

The (1R, 2S) isomer of Step 27a (9.86 g, 16.4 mmol) was treated with 1 N NaOH (50 mL, 50 mmol) in a mixture of THF (150 mL) and methanol (80 mL) for 12 h. The mixture was concentrated in vacuo until only the aqueous layer remained. Water (100 mL) was added and 1 N HCl was added slowly until pH = 3. The mixture was then extracted with ethyl acetate (3 × 200 mL) and the organic extract was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a white powder (9.2 g, 98% yield). ¹ H NMR (methanol-d ₄ ) δ 1.41 (s, 2H), 1.45 (s, 9H), 1.77 (dd, J = 7.9, 5.5 Hz, 1H), 2.16−2.21 (m, 1H), 2.44−2.51 (m, 1H), 2.74−2.79 (m, 1H), 3.93−3.96 (m, 2H), 3.98 (s, 3H), 4.44 (t, J = 7.9 Hz, 1H), 5.11 (d, J = 9.5 Hz, 1H), 5.30 (d, J = 17.1 Hz, 1H), 5.52 (s, 1H), 5.79−5.86 (m, 1H), 7.22 (dd, J = 9.16, 2.14 Hz, 1 H), 7.32 ( s, 1H), 7.43 (d, J = 2.14 Hz, 1H), 7.54-7.60 (m, 3H), 8.04 (dd, J = 7.8, 1.4 Hz, 2H), 8.08 (d, J = 9.1 Hz, 1H ); LC-MS (HPLC conditions "B", retention time: 1.46), MS m / z 574 (M + + l).

Step 27c: 2 (S)-(1 (R) -cyclopropanesulfonylamino-carbonyl-2 (S) -vinyl-cyclopropylcarbamoyl) -4 (R)-(7-methoxy-2-phenylquinoline-4- Preparation of (Iloxy) -pyrrolidine-1-carboxylic acid tert-butyl ester (below)

The product of step 27b (7.54 g, 13.14 mmol) was combined with CDI (3.19 g, 19.7 mmol) and DMAP (2.41 g, 19.7 mmol) in anhydrous THF and the resulting mixture was heated to reflux for 45 min. The slightly opaque mixture was allowed to cool to room temperature and to this was added cyclopropylsulfonamide (1.91 g, 15.8 g). Upon addition of DBU (5.9 mL, 39.4 mmol), the mixture became completely clear. The brown solution was stirred overnight. The mixture was then concentrated in vacuo to an oil and redissolved in ethyl acetate (500 mL). The solution was washed with pH = 4 buffer (3 × 200 mL) and the combined buffer washes were re-extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a beige solid. The crude product was purified by flash chromatography on a Biotage Flash 75M cartridge (25% hexane / ethyl acetate) to give the title compound (5.85 g, 66% yield). ¹ H NMR (methanol-d ₄ ) δ 1.03-1.09 (m, 2H), 1.15-1.28 (m, 2H), 1.40-1.44 (m, 2H), 1.46 (s, 9H), 1.87 (dd, J = 8.1, 5.6 Hz, 1 H), 2.21−2.27 (m, 1H), 2.36−2.42 (m, 1H), 2.65 (dd, J = 13.7, 6.7 Hz, 1H), 2.93−2.97 (m, 1H), 3.90−3.96 (m, 2H), 4.00 (s, 3H), 4.40 (dd, J = 9.5, 7.0 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 5.31 (d, J = 17.4 Hz, 1H), 5.64 (s, 1H), 5.73−5.80 (m, 1H), 7.30 (dd, J = 9.2, 2.1 Hz, 1H), 7.40 (s, 1H), 7.47 (s, 1H), 7.61−7.63 (m, 3H), 8.04−8.05 (m, 2H), 8.15 (d, J = 9.5 Hz, 1H); LCMS (HPLC condition “B”, retention time: 1.48), MS m / z 677 ( M ⁺ +1).

Step 27d: 4 (R)-(7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2 (S) -carboxylic acid (1 (R) -cyclopropanesulfonylaminocarbonyl-2 (S)- Preparation of vinyl-cyclopropyl) -amide (below)

The product of step 27c (5.78 g, 8.54 mmol) was treated with 4.0 M HCl in 1,4-dioxane (50 mL, 200 mmol) overnight. The reaction mixture was concentrated in vacuo and placed in a 50 ° C. vacuum oven for several days. There was thus obtained the bis-hydrochloride salt of the title compound as a beige powder (5.85 g, quantitative). ¹ H NMR (methanol-d ₄ ) δ 1.03-1-1.18 (m, 3H), 1.26-1.30 (m, 1H), 1.36-1.40 (m, 2H), 1.95 (dd, J = 8.2, 5.8 Hz, 1H) , 2.37 (q, J = 8.9 Hz, 1H), 2.51−2.57 (m, 1H), 2.94−2.98 (m, 1H), 3.09 (dd, J = 14.6, 7.3 Hz, 1H), 3.98 (d, J = 3.7 Hz, 1 H), 3.99 (s, 1 H), 4.08 (s, 3 H), 4.80 (dd, J = 10.7, 7.6 Hz, 1 H), 5.15 (dd, J = 10.2, 1.4 Hz, 1H), 5.32 (dd, J = 17.1, 1.2 Hz, 1H), 5.61−5.69 (m, 1H), 5.99 (t, J = 3.7 Hz, 1H), 7.51 (dd, J = 9.3, 2.3 Hz, 1H ), 7.59 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 7.72-7.79 (m, 3H), 8.09 (dd, J = 7.0, 1.5 Hz, 2H), 8.53 (d, J = 9.2 Hz, 1H); LC-MS (HPLC condition “B”, retention time: 1.01), MS m / z 577 (M ⁺ +1).

Step 27e: Preparation of Compound 95

Into a reaction vessel containing PS-DIEA resin (Argonaut Technologies, 0.047 g, 0.175 mmol), a solution of bicine (0.044 mmol) in DMF (0.25 mL), then compound 6 (0.020 g, 0.029 mmol) in DMF (0.50 mL). ), A solution of HATU (0.017 g, 0.044 mmol) in DMF (0.25 mL) was added. The mixture was shaken for 3 days at room temperature. PS trisamine resin (Argonaut Technologies, 0.025 g, 0.086 mmol) was added to the reaction and the mixture was shaken for 18 h at room temperature. The reaction mixture was concentrated in vacuo and redissolved in a 10: 1 mixture of 1,2-dichloroethane and methanol (1 mL). MP-carbonate resin (Argonaut Technologies, 0.056 g, 0.175 mmol) was added and the mixture was shaken for 5 days at room temperature. The reaction mixture was filtered, passed through 0.25 g of silica gel and eluted with 1.5 mL of 1,2-dichloroethane: methanol (10: 1). The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC (preparative HPLC method “A”) and separated as the bis-trifluoroacetate salt: LC-MS (HPLC condition “G” ”, Retention time: 1.16), MS m / z 722 (M ⁺ +1).

Example 28
Compound 96, 1- (2-acetylamino-pent-4-inoyl) -4 (R)-(7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2 (S) carboxylic acid (1 ( R) -Cyclopropanesulfonylaminocarbonyl-2 (S) -vinyl-cyclopropyl) amide (below)

This compound was prepared according to the method of Example 27, purified by preparative HPLC (Prep HPLC method “A”) and isolated as the monotrifluoroacetate salt. LC-MS (HPLC condition “G”, retention time: 1.28), MS m / z 714 (M ⁺ +1).

Example 29
Compound 97, {1S- [2S- (1R-cyclopropanesulfonylamino-carbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2-vinyl-cyclopropyl} -carbamic acid tert-butyl ester (below) was prepared as described in steps 29a-b.

Step 29a: Preparation of 4R- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropanesulfonylamino-carbonyl-2S-vinylcyclopropyl) amide (below)

The product of step 27c (505.0 mg, 0.746 mmol) was treated slowly with 50% TFA (10 mL) with controlled CO ₂ gas blowing vigorously. After stirring at rt for 0.5 hr, the solvent was concentrated and the resulting viscous brown oil was dried overnight under vacuum to give a brown solid in quantitative yield. The product was used without further purification. ¹ H NMR (methanol-d ₄ ) δ 1.03-1.06 (m, 1H), 1.07-1.13 (m, 1H), 1.14-1.19 (m, 1H), 1.25-1.30 (m, 1H), 1.37 ( dd, J = 9.6, 5.6 Hz, 1H), 1.96 (dd, J = 7.9, 5.5 Hz, 1H), 2.31 (q, J = 8.5 Hz, 1H), 2.52−2.58 (m, 1H), 2.93−3.01 (m, 2H), 3.94 (dd, J = 13.3, 4.0 Hz, 1H), 4.02 (dd, J = 13.3, 1.4 Hz, 1H), 4.07 (s, 3H), 4.76 (dd, J = 10.4, 7.6 Hz, 1H), 5.15 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 (dd, J = 17.3, 1.4 Hz, 1H), 5.61−5.69 (m, 1H), 5.96−5.98 (m, 1H) , 7.46 (dd, Lut 9.2, 1.4 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.71−7.79 (m, 3H), 8.05−8.07 (dd, J = 8.5, 1.5 Hz, 2H), 8.40 (d, J = 9.4 Hz, 1H); LC-MS ( retention time: 1.10), MS m / z 577 (M + + l);

Step 29b: Preparation of compound 97

To a solution of the product of step 29a (70. Omg, 0.087 mmol) in DCM (3 mL) was added DIEA (76 μL, 0.43 mmol), HBTU (40 mg, 0.104 mmol), HOBt (16 mg, 0.104 mmol) and amino-2. -Vinylcyclopropanecarboxylic acid (0.104 mmol) was added. 14 hr After stirring at rt, the solvent was concentrated and separated The resulting material was purified by flash column chromatography (elution with Si0 _2, DCM in 5% MeOH), 41% of the high RF isomer (IC ₅₀ = 250 nM, NMR not shown here as it was not clean) and 50% low RF isomer (IC ₅₀ = 24 nM)). ¹ H NMR (low RF isomer) (MeOH) δ 0.85-0.92 ( m, 1H), 0.97-1.03 (m, 3H), 1.06-1.10 (m, 1H), 1.15-1.21 (m, 2H), 1.26-1.33 (m, 2H), 1.38 (dd, J = 9.2, 4.6 Hz, 1H), 1.46 (s, 9H), 1.58−1.66 (m, 1H), 1.80 (t, J = 5.8 Hz, 1H), 1.86 (t, J = 6.3 Hz, 1H), 2.01 (q, J = 8.9 Hz, 1H), 2.40 (q, J = 7.9 Hz, 1H), 2.46−2.49 (m, 1H), 2.72 (dd, J = 13.7, 7.0 Hz, 1H), 2.84−2.94 (m, 1H) , 3.95 (s, 3H), 4.10 (s, 2H), 4.63−4.70 (m, 2H), 4.94−4.99 (m, 1H), 5.07 (d, J = = 10.4 Hz, 1H), 5.30 (d, J = 16.8 Hz, 1H), 5,54 (bs, 1H), 5.82-5.87 (m, 1H), 7.14 (dd, J = 9.2, 2.1 Hz, 1H), 7.21 (s, 1H), 7.39 (s , 1H), 7.50−7.56 (m, 3H), 7.98 (d, J = 8.9 Hz, 1H), 8.06 (cl, J = 6.7 Hz, 1H); LC-MS (retention time: 1.51), MS m / z 786 (M ⁺ +1).

Example 30
Compound 98, 1- (2S-acetylamino-3,3-dimethyl-butyryl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropanesulfonyl) Aminocarbonyl-2S-vinyl-cyclopropyl) amide (below) was prepared as described in steps 30a-c below.

Step 30a: {1S- [2S- (lR-cyclo-propanesulfonylamino-carbonyl-2S-vinylcyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} carbamic acid tert-butyl ester (below)

To a solution of DCM (10 mL) (step 29a (0.671 mmol), DIEA (542 μL, 3.36 mmol), HATU (354 mg, l. Olmmol), HOAt (127 mg, l. Olmmol) and Boc-Tle-OH (173 mg, After stirring at rt for 16 hr, the solvent was concentrated and the resulting brown viscous oil was purified by flash column chromatography (SiO ₂ , eluted with 95% MeOH in DCM) and slightly A yellow foamy solid was obtained (527 mg, 99% yield) LC-MS (retention time: 1.57), MS m / z 790 (M ⁺ +1).

Step 30b: 1S- (2-amino-3,3-dimethyl-butyryl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropane-sulfonyl) Preparation of aminocarbonyl-2S-vinylcyclopropyl) -amide (below)

The product of step 30a (950 mg, 1.20 mmol) was treated slowly with 25% TFA (25 mL) with vigorous control of CO ₂ gas. After stirring at rt for 1.5 hr, the solvent was concentrated to obtain a light brown solution slurry, which was precipitated by adding Et ₂ O. A light brown product (l.lOg 99% yield) was obtained by vacuum filtration and used without further purification. LC-MS (retention time: 1.13), MS m / z 690 (M ⁺ +1).

Step 30c: Preparation of Compound 98
To a solution of the product of step 30b (11.1 mg, 0.0121 mmol) in DCM (1 mL) was added polyvinylpyridine (6.4 mg, 0.0605 mmol) and acetic anhydride (30 μL). The reaction vial was allowed to stir for 14 h and the contents were filtered and washed with DCM. The solvent was concentrated and the residue was purified by reverse phase preparative HPLC to give a white glassy solid (4.0 mg, 45% yield) as a TFA salt. ¹ H NMR (MeOH) δ 1.06 (s, 9H), 1.08-1.10 (m, 2H), 1.23-1.26 (m, 2H), 1.45 (dd, J = 9.5, 5.5 Hz, 1H), 1.81 (s, 3H), 1.90 (dd, J = 7.9, 5.5 Hz, 1H), 2.25 (q, J = 8.9 Hz, 1H), 2.24−2.46 (m, 1H), 2.75 (dd, J = 14.2, 6.9 Hz, 1H ), 2.93−2.98 (m, 1H), 4.06 (s, 3H), 4.17 (dd, J = 12.4, 3.2 Hz, 1H), 4.50 (t, J = 4.3 Hz, 1H), 4.57−4.61 (m, 2H), 5.14 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 (dd, J = 17.2, 1.4 Hz, 1H), 5.71−5.78 (m, 1H), 5.86 (d, J = 3.1, 1H) , 4.45 (dd, J = 9.2, 2.4 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.71−7.79 (m, 3H), 8.08 (dd, J = 8.2 , 1.5 Hz, 3H), 8.30 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.35), MS m / z 732 (M ⁺ +1).

Example 32
The following compounds were prepared according to the method of Example 30.
Compound 99
Compound 99, 1- [3,3-dimethyl-2S- (2,2,2-trifluoro-acetylamino) -butyryl] -4R- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2S -Carboxylic acid (lR-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 99 was prepared using anhydrous fluoroacetic acid.
¹ H NMR (MeOH) δ 0.99-1.03 (m, 4H), 1.09 (s, 9H), 1.23-1.26 (m, 3H), 1.46 (dd, J = 9.5, 5.2 Hz, 1H), 1.91 (dd, J = 8.2, 5.5 Hz, 1H), 2.24 (q, J = 9.0 Hz, 1H), 2.41−2.47 (m, 1H), 4.06 (s, 3H), 4.16 (dd, J = 12.5, 3.1 Hz, 1H ), 4.59−4.63 (m, 3H), 5.14 (dd, J = 10.2, 1.7 Hz, 1H), 5.30 (dd, J = 17.3, 1.1 Hz, 1H), 5.72−5.79 (m, 1H), 5.87 ( d, J = 4.0, 1H), 7.40 (dd, J = 9.2, 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 7.73-7.79 (m, 4H) , 8.08 (d, J = 6.7 Hz, 3H), 8.29 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.50), MS m / z 786 (M ⁺ +1).

Compound 100
Compound 100, N- {1S- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine- 1-carbonyl] -2,2-dimethyl-propyl} -succinamic acid (below)

Compound 100 was prepared using succinic anhydride. ¹ H NMR (MeOH) δ 1.04-1.09 (m, 2H), 1.10 (s, 9H), 1.23-1.25 (m, 2H), 1.44 (dd, J = 9.5, 5.5 Hz, 1H), 1.90 (dd, J = 8.2, 5.5 Hz, 1H), 2.20−2.29 (m, 4H), 2.39−2.50 (m, 2H), 2.76 (d, J = 6.71 Hz, 1H), 2.93−2.98 (m, 1H), 4.06 (s, 3H), 4.12 (dd, J = 12.7, 3.2 Hz, 1H), 4.49 (d, J = 5.2 Hz, 1H), 4.59 (dd, J = 0.2, 6.9 Hz, 1H), 4.65 (d, J = 11.9 Hz, 1H), 5.14 (dd, J = 10.6, 1.5 Hz, 1H), 5.31 (dd, J = 17.1, 1.2 Hz, 1H), 5.71−5.78 (m, 1H), 5.85 (d, J = 3.1 Hz, 1H), 7.47 (dd, J = 9.3, 2.3 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.71-7.79 (m , 3H), 8.08 (d, J = 7.0 Hz, 2H), 8.31 (dd, J = 11.6, 2.5 Hz, 1H); LC-MS (retention time: 1.31), MS m / z 790 (M ⁺ +1 ).

Compound 101
Compound 101, 1- [2S- (2,2-dimethylpropionylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carvone Acid (lR-cyclo-propanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) -amide (below)

Compound 101 was prepared using trimethylacetyl chloride. ¹ H NMR (MeOH) δ 1.01 (bs, 9H), 1.02-1.04 (m, 4H), 1.05 (bs, 9H), 1.23-1.29 (m, 5H), 1.49 (dd, J = 9.6, 6.5 Hz, 1H), 1.90 (dd, J = 8.1, 5.7 Hz, 1H), 2.40−2.47 (m, 1H), 2,72−2.79 (m, 1H), 2.92−2.96 (m, 1H), 4.06 (s, 3H), 4.20 (d, J = 12.5 Hz, 1H), 4.54−4.60 (m, 3H), 5.14 (dd, J = 10.5, 1.7 Hz, 1H), 5.32 (dd, J = 17.4, 1.0 Hz, 1H ), 5.75−5.82 (m, 1H), 6.92 (d, J = 8.9 Hz, 1H), 7.40−7.43 (m, 1H), 7.54 (t, J = 2.3 Hz, 1H), 7.66 (d, J = 3.1 Hz, 1H), 7.72-7.78 (m, 4H), 8.07-8.10 (m, 2H), 8.31 (dd, J = 9.2, 2.7 Hz, 1H); LC-MS (retention time: 1.54), MS m / z 774 (M ⁺ +1).

Example 33
Compound 102
Compound 102, 1- [2S- (2-hydroxy-acetylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclo-propanesulfonylamino-carbonyl-2S-vinyl-cyclopropyl) amide (below)

To a solution of the product of step 30b (ll. Lmg, 0.0121 mmol) in DCM (lmL), DIEA (llpL, 0.0605 mmol), HATU (6.9 mg, 0.0182 mmol), HOAt (2.5 mg, 0.01812 mmol) and glycolic acid (1.4 mg, 0.0182 mmol) was added. After stirring at rt for 16 hr, the solvent and excess DIEA were concentrated, and the resulting residue was purified by reverse phase preparative HPLC to give a white solid (3.5 mg, 39% yield) as a TFA salt. ¹ H NMR (MeOH) δ 1.06-1.07 (m, 2H), 1.07 (s, 9H), 1.22-1.25 (m, 2H), 1.45 (dd, J = 9.6, 5.3 Hz, 1H), 1.90 (dd, J = 8.2, 5.5 Hz, 1H), 2.24 (q, J = 8.9 Hz, 1H), 2.42−2.47 (m, 1H), 2.76 (dd, J = 7.3 Hz, 1H), 2.92−2.98 (m, 1H ), 3.74 (d, J = 16.5 Hz, 1H), 3.90 (d, J = 16.2 Hz, 1H), 4.60 (s, 3H), 4.19 (dd, J = 12.5, 3.4 Hz, 1H), 4.56−4.61 (m, 3H), 5.14 (d, J = 10.4 Hz, 1H), 5.30 (d, J = 17.1 Hz, 1H), 5.72−5.79 (m, 1H), 5.86 (bs, 1H), 7.45 (dd, J = 9.3, 2.3 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.64 (s, 1H), 7.72-7.79 (m, 4H), 8.08 (d, J = 7.0 Hz, 2H), 8.28 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.30), MS m / z 748 (M ⁺ +1).

Example 34
The following compound was prepared according to the method of Example 33.

Compound 103
Compound 103, 1- [2S- (3,3-dimethyl-butyrylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carvone Acid (lR-cyclo-propanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 103 was prepared using t-butylacetic acid. ¹ H NMR (MeOH) δ 0.78 (s, 9H), 0.90-0.98 (m, 2H), 1.04 (s, 9H), 1.23-1.29 (m, 5H), 1.45 (dd, J = 9.5, 5.5 Hz, 1H), 1.86−1.91 (m, 2H), 1.97 (d, J = 12.8 Hz, 1H), 2.24 (d, 8.9 Hz, 1H), 2.39−2.45 (m, 1H), 2.76 (dd, J = 13.6 , 6.0 Hz, 1H), 2.93−2.97 (m, 1H), 4.06 (s, 3H), 4.16 (dd, J = 12.4, 2.9 Hz, 1H), 4.52 (t, J = 4.4 Hz, 1H), 4.60 (dd, J = 10.5, 6.9 Hz, 1H), 4.65 (dd, J = 13.3, 1.1 Hz, 1H), 5.14 (dd, J = 10.5, 1.4 Hz, 1H), 5.31 (dd, J = 17.2 , 1.1 Hz, 1H), 5.72−5.79 (m, 1H), 5.85 (bs, 1H), 7.42 (dd, J = 9.3, 2.3 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.66 (s, 1H), 7.72-7.79 (m, 4H), 8.08 (d, J = 7.0 Hz, 3H), 8.30 (d, J = 9.2 Hz, 2H); LC-MS (retention time: 1.58), MS m / z 788 (M ⁺ +1).

Compound 104
Compound 104, 1- [2S- (2-cyclopropyl-acetylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carvone Acid (lR-cyclo-propanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) -amide (below)

Compound 104 was prepared using cyclopropylacetic acid. ¹ H NMR (MeOH) δ 0.07-0.10 (m, 2H), 0.39-0.34 (m, 2H), 0.77-0.82 (m, 1H), 1.00-1.07 (m, 4H), 1.08 (s, 9H), 1.21-1.26 (m, 3H), 1.46 (dd, J = 9.6, 5.3 Hz, 1H), 1.90 (dd, J = 8.2, 5.5 Hz, 1H), 1.96-2.02 (m, 2H), 2.25 (dd, J = 17.7, 8.6 Hz, lH), 2.43−2.46 (m, 1H), 2.78 (dd, J = 13.9, 6.6 Hz, 1H), 2.92−2.98 (m, 1H), 4.07 (s, 3H), 4.19 (dd, J = 12.5, 3.4 Hz, 1H), 4.55 (s, 1H), 4.60 (dd, J = 10.7, 7.7 Hz, 2H), 5.15 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 ( dd, J = 17.2, 1.4 Hz, 1H), 5.72−5.87 (m, 1H), 5.87 (d, J = 3.4 Hz, 1H), 7.42 (dd, J = 9.3, 2.3 Hz, 1H), 7.54 (d , J = 2.4 Hz, 1H), 7.65 (s, 1H), 7.72-7.79 (m, 4H), 8.09 (d, J = 7.6 Hz, 2H), 8.30 (d, J = 9.2 Hz, 1H); LC -MS (retention time: 1.49), MS m / z 772 (M ⁺ +1).

Compound 105
Compound 105, 1- {2S-[(bicyclo [1.1.1] pentane-2-carbonyl) -amino] -3,3-dimethyl-butyryl} -4R- (7-methoxy-2-phenyl-quinoline- 4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 105 was prepared using bicyclo [1.1.1] pentane-2-carboxylic acid. ¹ H NMR (MeOH) δ 1.05 (s, 9H), 1.06-1.10 (m, 4H), 1.23-1.26 (m, 2H), 1.44-1.48 (m, 1H), 1.60-1.62 (m, 1H), 1.68 (d, J = 2.4 Hz, lH), 1.91 (dd, J = 7.7, 4.7 Hz, 1H), 2.01 (dd, J = 9.8, 3.1 Hz, 1H), 2.22−2, 27 (m, 1H) , 2.40−2.46 (m, 1H), 2.55−2.60 (m, 2H), 2.75−2.81 (m, 1H), 2.92−2.98 (m, 1H), 4.06 (s, 3H), 4.16 (dd, J = 12.7, 3.2 Hz, 1H), 4.57−4.64 (m, 3H), 5.15 (dd, J = 10.4, 1.5 Hz, 1H) 5.32 (dd, J = 17.4, 1.5 Hz, 1H), 5.74−5.80 (m, 1H), 5.87 (d, J = 2.1 Hz, 1H), 7.39−7.42 (m, 1H), 7.53 (t, J = 2.3 Hz, 1H), 7.72−7.78 (m, 4H), 8.06−8.10 (m , 2H), 8.30 (dd, J = 9.2, 3.8 Hz, 1H). LC-MS (retention time: 1.52), MS m / z 784 (M ⁺ +1).

Example 35
Compound 106
Compound 106, acetic acid {lS- [2S- (lR-cyclopropane-sulfonylaminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1 -Carbonyl] -2,2-dimethyl-propylcarbamoyl} -methyl ester (below)

To a solution of the product of step 30b (35. Omg, 0.0381 mmol) in DCM (2 mL) was added DIEA (40pL, 0.0191 mmol), HATU (29 mg, 0.0762 mmol) and acetoacetic acid (6.7 mg, 0.0572 mmol). . After stirring at rt for 16 hr, the solvent was concentrated, and the resulting residue was purified with a flash column (SiO ₂ , eluted with 5% MeOH in DCM) to give a yellow solid (30 mg, 99% yield). ¹ H NMR (MeOH) δ 0.87-0.93 (m, 1H), 0.96-1.02 (m, 1H), 1.06 (s, 11H), 1.20-1.26 (m, 2H), 1.27-1.29 (M, 1H), 1.45 (dd, J = 9.5, 5.2 Hz, 1H), 1.87 (dd, J = 7.9, 5.5 Hz, 1H), 2.08 (s, 3H), 2.22 (q, J = 8.9 Hz, 1H), 2.33−2.36 (m, 1H), 2.66 (dd, J = 13.1, 6.9 Hz, 1H), 2.92−2.96 (m, 1H), 3.22 (q, J = 7.3 Hz, 2H), 3.69−3.76 (m, 2H), 3.95 (s, 3H), 4.16 (dd, J = 12.1, 3.5 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 4.48 (s, 2H), 4.52 (dd, J = 10.1, 6.7 Hz , 1H), 4.67 (s, 1H), 5.11 (d, J = 10.4 Hz, 1H), 5.29 (d, J = 17.1 Hz, 1H), 5.59 (bs, 1H), 5.73-5.80 (m, 1H) , 7.17 (dd, J = 9.0, 2.3 Hz, 1H), 7.27 (s, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.49−7.56 (m, 3H), 8.04 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 6.7 Hz, 2H); LC-MS (retention time: 1.33), MS m / z 790 (M ⁺ +1).

Example 36
The following compound was prepared according to the method of Example 35.

Compound 107
Compound 107, 1- [2S- (2-methoxy-acetylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (lR-cyclo-propanesulfonylamino-carbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 107 was prepared using methoxyacetic acid and purified by reverse phase preparative HPLC to give a white solid (18.8 mg, 56% yield) as a TFA salt. ¹ H NMR (MeOH) δ 1.04-1.12 (m, 2H), 1.06 (s, 9H), 1.24-1.26 (m, 2H), 1.37 (dd, J = 6.4, 4.0 Hz, 1H), 1.46 (dd, J = 9.5, 5.5 Hz, 1H), 1.90 (dd, J = 8.2, 5.5 Hz, 1H), 2.24 (q, J = 8.9 Hz, 1H), 2.39−2.45 (m, 1H), 2.74 (dd, J = 13.3, 7.2 Hz, 1H), 2.93−2.96 (m, 1H), 3.34 (s, 3H), 3.73 (dd, J = 74.2, 15.2 Hz, 2H), 4.05 (s, 3H), 4.18 ( dd, J = 12.5, 3.1 Hz, 1H), 4.56−4.60 (m; 3H), 5.14 (dd, J = 10.2, 1.5 Hz, 1H), 5.31 (dd, J = 16.8, 1.2 Hz, 1H), 5.73 −5.80 (m, 1H), 5.82 (bs, 1H), 7.39 (dd, J = 9.2, 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.58 (s, 1H), 7.61 ( d, J = 9.2 Hz, 1H), 7.69−7.72 (m, 3H), 8.08 (dd, J = 7.9, 1.5 Hz, 1H), 8.24 (dd, J = 9.2 Hz, 1H); LC-MS (holding) Time: 1.35)., MS m / z 762 (M ⁺ +1).

Compound 108
Compound 108, 1- {2S- [2- (4-methoxy-phenoxy) acetylamino] -3,3-dimethyl-butyryl} -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine -2S-carboxylic acid (lR-cyclopropanesulfonylamino-carbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 108 was prepared using 4-methoxyphenoxyacetic acid. ¹ H NMR (MeOH) δ 1.04 (s, 9H), 1.08-1.10 (m, 2H), 1.23-1.27 (m, 2H), 1.47 (dd, J = 9.5, 5.5 Hz, 1H), 1.91 (dd, J = 8.2, 5.5 Hz, 1H), 2.24 (q, J = 8.9 Hz, 1H), 2.41−2.47 (m, 1H), 2.76 (dd, J = 13.7, 7.0 Hz, 1H), 2.93−2.98 (m , 1H), 3.73 (s, 3H), 4.02 (s, 3H), 4.18 (dd, J = 12.4, 3.2 Hz, 1H), 4.23 (d, J = 15.0 Hz, 1H), 4.37 (d, J = 15.0 Hz, 1H), 4.58−4.62 (m, 3H), 5.14 (d, J = 10.4 Hz, 1H), 5.31 (d, J = 16.2 Hz, 1H), 5.73−5.81 (m, 1H), 5.86 ( bs, 1H), 6.85 (d, J = 5.5 Hz, 4H), 7.33 (dd, J = 9.2, 2.4 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.71−7.78 (m, 3H), 7.82 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 9.5 Hz, 1H); LC-MS (holding) Time: 1.54), MS m / z 854 (M ⁺ +1).

Compound 109
Compound 109, 1- {2S- [2- (4-fluoro-phenoxy) acetylamino] -3,3-dimethyl-butyryl} -4R- (7-methoxy-2phenyl-quinolin-4-yloxy) -pyrrolidine- 2S-carboxylic acid (lR-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) -amide (below)

Compound 109 was prepared using 4-fluorophenoxyacetic acid. ¹ H NMR (MeOH) δ 1.04 (s, 3.6 H), 1.05 (s, 5.4H), 1.07-1.10 (m, 2H), 1.22-1.27 (m, 2H), 1.44-1.48 (m, 1H) , 1.88-1.92 (m, 1H), 2.21-2.26 (m, 1H), 2.41-2.47 (m, 1H), 2.76 (dd, J = 13.4, 6.7 Hz, 1H), 2.93-2.97 (m, 1H), 4.01 (s, 1.2H), 4.02 (s, 1.8H), 4.16−4.20 (m, 1H), 4.28 (d, J = 5.2 Hz, 0.4H), 4.31 (d, J = 5.2 Hz, 0.6H), 4.40 (d, J = 5.2 Hz, 0.6H), 4.41 (d, J = 5.2 Hz, 0.4H), 4.58−4.62 (m, 3H), 5.12−5.15 (m, 1H), 5.30 (dd, J = 17.1, 0.91 Hz, 0.4H), 5.31 (dd, J = 17.1, 1.2 Hz, 0.6H), 5.73−5.81 (m, 1H), 5.86 (bs, 1H), 6.88−6.92 ( m, 2H), 6.97−7.02 (m, 2H), 7.31-7.35 (m, 1H), 7.49 (d, J = 2.4 Hz, 0.4H), 7.50 (d, J = 2.4 Hz, 0.6H), 7.63 (s, 0.4H), 7.64 (s, 0.6H), 7.70−7.77 (m, 3H), 7.86−7.89 (m, 1H), 8.05−8.08 (m, 2H), 8.4 (d, J = 9.5 Hz, 0.4H), 8.5 (d, J = 9.2 Hz, 0.6H); LC-MS (retention time: 1.56), MS m / z 842 (M ⁺ +1).

Compound 110
Compound 110, 1- {2S-[(furan-2-carbonyl) -amino] -3,3-dimethyl-butyryl} -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S -Carboxylic acid (lR-cyclo-propanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 110 was prepared using furan carboxylic acid. ¹ H NMR (MeOH) δ 1.09 (s, 3.6H), 1.10 (s, 5.4H), 1.11-1.15 (m, 2H), 1.25-1.28 (m, 2H), 1.47 (q, J = 5.5 Hz, 1H), 1.91 (q, J = 5.5 Hz, 1H), 2.25 (q, J = 8.9 Hz, 1H), 2.42−2.47 (m, 1H), 2.79 (dd, J = 14.7, 7.5 Hz, 1H), 2.95−2.99 (m, 1H), 4.04 (s, 1.2H), 4.05 (s, 1.8H), 4.14−4.19 (m, 1H), 4.61−4.66 (m, 1H), 4.73 (d, J = 9.2 Hz, 1H), 5.15 (dd, J = 10.1, 0.9 Hz, 1H), 5.32 (d, J = 17.4 Hz, 0.6 H), 5.33 (d, J = 16.5 Hz, 0.4H), 5.74−5.81 ( m, 1H), 5.87 (bs, 1H), 6.52−6.53 (m, 1H), 6.85 (d, J = 3.4 Hz, 1H), 7.28 (dd, J = 9.2, 2.5 Hz, 1H), 7.48 (dd , J = 8.6, 2.4 Hz, 1H), 7.60−7.66 (m, 2H), 7.73−7.78 (m, 3H), 7.85 (d, J = 8.9 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.42), MS m / z 784 (M ⁺ +1).

Compound 111
Compound 111, 1- {2S-[(1-hydroxy-cyclopropane-carbonyl) -amino] -3,3-dimethyl-butyryl} -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine -2S-carboxylic acid (lR-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 111 was prepared using 1-hydroxy-1-cyclopropanecarboxylic acid. ¹ H NMR (MeOH) δ 0.64−0.68 (m, 1H), 0.79−0.84 (m, 1H), 0.89−0.93 (m, 1H), 0.99−1.04 (m, 1H), 1.04−1.08 (m, 2H ), 1.09 (s, 9H), 1.23-1.26 (m, 2H), 1.45 (dd, J = 9.5, 5.2 Hz, 1H), 1.91 (dd, J = 8.2, 5.5 Hz, 1H), 2.25 (q, J = 8.9 Hz, 1H), 2.41−2.47 (m, 1H), 2.76 (dd, J = 14.2, 6.9 Hz, 1H), 2.93−2.97 (m, 1H), 4.06 (s, 3H), 4.17 (dd , J = 12.4, 3.2 Hz, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.59−4.62 (m, 2H), 5.14 (dd, J = 10.4,1.5 Hz, 1H), 5.31 (dd, J = 17.1, 1.2 Hz, 1H), 5.72−5.79 (m, 1H), 5.85 (bs, 1H), 7.41 (dd, J = 9.3, 2.3 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H ), 7.63 (s, 1H), 7.71-7.78 (m, 4H), 8.07 (dd, J = 6.7, 1.5 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H); LC-MS (retention time) : 1.33), MS m / z 774 (M ⁺ +1).

Compound 112
Compound 112, 1- [2S- (2-fluoro-acetylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (lR-cyclo-propanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 112 was prepared using sodium fluoroacetate. ¹ H NMR (MeOH) δ 1.08 (s, 9H), 1.03-1.12 (m, 3 H), 1.22-1.26 (m, 2H), 1.45 (q, J = 5.5 Hz, 1H), 1.9O ( q, J = 5.5 Hz, 1H), 2.25 (q, J = 8.9 Hz, 1H), 2.41−2.27 (m, 1H), 2.27 (dd, J = 14.0, 6.7 Hz, 1H), 2.92−2.97 (m , 1H), 3.97 (s, lH), 4.06 (s, 3H), 4.19 (dd, J = 12.5, 3.1 Hz, 1H), 4.58−4.62 (m, 3H), 4.64 (q, J = 14.0 Hz, 1H), 4.73 (q, J = 14.0 Hz, 1H), 5.14 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 (dd, J = 17.1, 1.2 Hz, 1H), 5.71−5.77 (m, 1H ), 5.87 (bs, 1H), 7.44, J = 9.2, 2.4 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.71-7.79 (m, 3H), 8.08 (dd, J = 8.5, 1.5 Hz, 2H), 8.31 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.42), MS m / z 750 (M ⁺ +1).

Example 37
Compound 113
Compound 113, {1S- [2S- (1R-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1-carbonyl ] -2,2-Dimethyl-propyl} carbamic acid methyl ester (below)

To a solution of the product of step 30b (35 mg, 0.0381 mmol) in DCM (2 mL) was added 1,3-dimethylperhydro-1,2,3-diazaphosphine (lOOmg, 2.3 mmol / g, 0.229 mmol) on polystyrene. And methyl chloroformate (9 L, 0.114 mmol) was added. The reaction vial was rotated for 16 h, filtered and washed with DCM. The solvent was concentrated and the residue was purified by reverse phase preparative HPLC to give a white solid product as a TFA salt (14.7 mg, 35% yield). ¹ H NMR (MeOH) δ 1.05 (s, 9H), 1.07-1.11 (m, 2H), 1.22-1.26 (m, 2H), 1.44 (q, J = 5.2 Hz, 1H), 1.90 (q, J = 5.7 Hz, 1H), 2.24 (q, J = 8.7 Hz, 1H), 2.40−2.46 (m, 1H), 2.77 (dd, J = 13.9, 6.9 Hz, lH), 2.92−2.97 (m, 1H) 3.38 (s, 3H), 4.06 (s, 3H), 4.14 (dd, J = 12.2, 3.1 Hz, 1H), 4.23 (s, 1H), 4.58−4.64 (m, 2H), 5.13 (dd, J = 10.4 , 1.5 Hz, 1H), 5.30 (dd, J = 17.1, 1.2 Hz, 1H), 5.70−5.77 (m, 1H), 5.86 (bs, 1H), 7.43 (dd, J = 9.3, 2.3 Hz, 1H) , 7.54 (d, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.72−7.79 (m, 3H), 8.09 (dd, J = 6.9, 1.7 Hz, 1H), 8.36 (d, J = 9 5 Hz, 1H); LC-MS (retention time: 1.47), MS m / z 748 (M ⁺ +1)

Example 38
The following compound was prepared according to the method of Example 37.
Compound 114
Compound 114, [1S- [2S- (1R-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1-carbonyl ] -2,2-Dimethyl-propyl} -carbamic acid benzyl ester (below)

Compound 114 was prepared using benzyl chloroformate. ¹ H NMR (MeOH) δ 1.05 (s, 9H), 1.06-1.09 (m, 2H), 1.23-1.24 (m, 2H), 1.45 (q, J = 5.5 Hz, 1H), 1.90 (q, J = 5.5 Hz, 1H), 2.25 (q, J = 8.7 Hz, 1H), 2.40−2.46 (m, 1H), 2.77 (dd, J = 13.4, 7.0 Hz, 1H), 2.92−2.97 (m, 1H), 3.98 (s, 3H), 4.12 (dd, J = 12.2, 2.4 Hz, 1H), 4.23 (s, 1H), 4.59−4.73 (m, 4H), 5.14 (dd, J = 10.2, 1.4 Hz, 1H) , 5.31 (d, J = 17.1 Hz, 1H), 5.71−5.67 (m, 1H), 5.86 (bs, 1H), 7.15 (dd, J = 7.3, 1.8 Hz, 1H), 7.27 (d, J = 6.7 Hz, 1H), 7.32 (dd, J = 9.3, 2.0 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.72-7.79 (m, 3H), 8.07 (d , J = 7.0 Hz, 1H), 8.31 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.67), MS m / z 824 (M ⁺ + l)

Compound 115
Compound 115, {lS- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} -carbamic acid ethyl ester (below)

Compound 115 was prepared using ethyl chloroformate. ¹ H NMR (MeOH) δ 1.04 (s, 9H), 1.06-1.11 (m, 4H), 1.23-1.28 (m, 2H), 1.44 (q, J = 5.5 Hz, 1H), 1.90 (q, J = 5.5 Hz, 1H), 2.24 (q, J = 8.7 Hz, 1H), 2.39−2.45 (m, 1H), 2.76 (dd, J = 14.5, 6.9 Hz, 1H), 2.92−2.97 (m, 1H), 4.05 (s, 3H), 4.13 (dd, J = 12.2, 2.8 Hz, 1H), 4.58−4.63 (m, 2H), 5.14 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 (d, J = 17.1 Hz, 1H), 5.71−5.78 (m, 1H), 5.84 (bs, 1H), 7.39 (dd, J = 9.3, 2.0 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.62 ( s, 1H), 7.70-7.75 (m, 3H), 8.08 (dd, J = 7.9, 1.5 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.53), MS m / z 762 (M ⁺ +1).

Compound 116
Compound 116, {lS- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} -carbamic acid phenyl ester (below)

Compound 116 was prepared using phenyl chloroformate. ¹ H NMR (MeOH) δ 1.01-1.10 (m, 5H), 1.13 (s, 7H), 1.23-1.26 (m, 2H), 1.42-1.47 (m, 1H), 1.90 (dd, J = 7.8, 6.0 Hz, 1H), 2.25 (q, J = 8.7 Hz, 1H), 2.39−2.45 (m, 1H), 2.76 (dd, J = 13.9, 6.9 Hz, 1H), 2.93−2.97 (m, 1H), 4.03 (s, 2H), 4.06 (s, 1H), 4.11 (dd, J = 12.4, 2.9 Hz, 0.7H), 4.16 (dd, J = 12.7, 2.9 Hz, 0.3 H), 4.62 (q, J = 7.8 Hz, 1H), 4.69 (d, J = 12.5 Hz, 1H), 5.14 (d, J = 10.4 Hz, lH), 5.31 (d, J = 17.1 Hz, 1H), 5.69−5.77 (m, 1H), 5.81 (bs, 0.7H), 5.87 (bs, 0.3H), 6.92 (d, J = 7.93 Hz, 1H), 7.04 (dd, J = 9.3, 2.3 Hz, 1H), 7.21 (t, J = 7.3 Hz , 0.70H), 7.30 (t, J = 7.8 Hz, 1.4H), 7.41 (d, J = 2.4 Hz, 0.7H), 7.55 (d, J = 2.1 Hz, 0.3H), 7.57 (s, 0.7H ), 7.65 (s, 0.3H), 7.69-7.77 (m, 3H), 8.01 (d, J = 7.3 Hz, 1.4H), 8.08 (d, J = 7.0 Hz, 0.6H), 8.28 (t, J = 9.2 Hz, 1H) .. LC-MS (retention time: 1.62), MS m / z 810 (M ⁺ +1).

Compound 117
Compound 117, 1- (2S-methanesulfonylamino-3,3-dimethyl-butyryl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (lR-cyclo- Propanesulfonylamino-carbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 117 was prepared using methanesulfonyl chloride. ¹ H NMR (MeOH) δ 1.09-1.12 (m, 2H), 1.08 (s, 9H), 1.23-1.26 (m, 2H), 1.45 (dd, J = 9.5, 5.5 Hz, 1H), 1.90 (dd, J = 7.9, 5.5 Hz, 1H), 2.23 (q, J = 8.7 Hz, 1H), 2.40−2.47 m, 1H), 2.74 (s, 3H), 2.78 (dd, J = 14.0, 7.0 Hz, 1H) , 2.93−2.96 (m, 1H), 4.01 (s, 1H), 4.06 (s, 3H), 4.10 (dd, J = 12.5, 3.1 Hz, 1H), 4.58 (d, J = 14.4 Hz, 1H), 4.61 (dd, J = 10.4, 6.7 Hz, 1H), 5.15 (dd, J = 10.5, 1.4 Hz, 1H), 5.31 (dd, J = 17.0, 1.2 Hz, 1H), 5.71−5.78 (m, 1H) , 7.45 (dd, J = 9.2, 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.71−7.79 (m, 3H), 8.06 (dd, J = 6 9, 1.7 Hz, 1H), 8.37 (d,
J = 9.5 Hz, 1H); LC-MS (retention time: 1.38), MS m / z 768 (M ⁺ +1).

Compound 118
Compound 118, 1- (2S-cyclopropanesulfonylamino-3,3-dimethyl-butyryl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclo- Propanesulfonylamino-carbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 118 was prepared using cyclopropanesulfonyl chloride. ¹ H NMR (MeOH) δ 0.73-0.78 (m, 2H), 0.83-0.91 (m, 2H), 1.06-1.10 (m, 2H), 1.08 (s, 9H), 1.22-1.26 (m, 2H), 1.45 (dd, J = 9.5, 5.5 Hz, 1H), 1.90 (dd, J = 7.9, 5.5 Hz, 1H), 2.25 (q, J = 8.9 Hz, 1H), 2.32−2.36 (m, 1H), 2 41−2.47 (m, 1H), 2.79 (dd, J = 13.9, 6.7 Hz, 1H), 2.92−2.96 (m, 1H), 3.95 (s, 1H), 4.06 (s, 3H), 4.13 (dd, J = 12.4, 2.9 Hz, 1H), 4.52 (d, J = 12.5 Hz, 1H), 4.61 (q, J = 7.0 Hz, 1H), 5.14 (dd, J = 10.4, 1.5 Hz, 1H ), 5.31 (dd, J = 17.2, 1.4 Hz, 1H), 5.71−5.76 (m, 1H), 5.81 (bs, 1H), 7.43 (dd, J = 9.5, 2.5 Hz, 1H), 7.54 (dd, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.71-7.79 (m, 3H), 8.07 (dd, J = 7.0, 1.5 Hz, 1H), 8.36 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.44), MS m / z 794 (M ⁺ +1).

Compound 119
Compound 119, 1- [2S- (4-fluoro-benzenesulfonylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenylquinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropyl) amide (below)

Compound 119 was prepared using 4-fluorobenzenesulfonyl chloride. ¹ H NMR (MeOH) δ 0.93 (s, 3.6H), 1.01 (s, 2H), 1.08 (s, 5.4H), 1.22-1.26 (m, 2H), 1.41-1.47 (m, 1H), 1.85− 1.91 (m, 1H), 2.22−2.27 (m, 1H), 2.40−2.46 (m, 1H), 2.75 (dd, J = 014.0, 7.3 Hz, 0.4H), 2.79 (dd, J = 14.7, 7.6 Hz , 0.6H), 2.91 (m, 1H), 4.0 (s, 1H), 4.05 (s, 3H), 4.15 (t, J = 3.5 Hz, 0.4H), 4.17 (t, J = 3.7 Hz, 0.6H ) 4.44 (d, J = 12.5 Hz, 10.4H), 4.47−4.51 (m, 1H), 4.58 (d, J = 12.5 Hz, 0.6H), 4.60−4.64 (m, 1H), 5.13 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 (d, J = 17.1, 12.1 Hz, 1H), 5.68−5.78 (m, 1H), 5.83 (bs, 0.6H), 5.87 (bs, 0.4H), 7.07− 7.12 (m, 1H), 7.40 (dd, J = 9.2, 2.4 Hz, 0.4H), 7.44 (dd, J = 9.2, 2.4 Hz, 0.6H), 7.55 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 6.7 Hz, 1H), 7.71−7.81 (m, 4H), 7.93 (d, J = 8.5 Hz, 0.6H), 8.07−8.11 (m, 2H), 8.18 (d, J = 9.2 Hz, 0.4H), 8.28 (d, J = 9.5 Hz, 0.6H), 8.41 (d, J = 9.5 Hz, 0.4H); LC-MS (retention time: 1.35), MS m / z 732 (M ⁺ +1).

Compound 120
Compound 120, 1- [2S- (2-chloro-acetylamino) -3,3-dimethyl-butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropanesulfonylaminocarbonyl-2S-vinylcyclopropyl) -amide (below)

Compound 120 was prepared using chloroacetic anhydride. ¹ H NMR (MeOH) δ 1.04-1.11 (m, 3H), 1.08 (s, 9H), 1.22-1.25 (m, 2H), 1.44 (q, J = 5.2 Hz, 1H), 1.90 (q, J = 5.5 Hz, 1H), 2.24 (q, J = 8.8 Hz, 1H), 2.40−2.46 (m, 1H), 2.77 (dd, J = 14.2, 6.6 Hz, 1H), 2.92−2.97 (m, 1H), 3.91 (d, J = 13.1 Hz, 1H), 3.99 (d, J = 13.4 Hz, 1H), 4.06 (s, 3H), 4.16 (dd, J = 12.4,3.2 Hz, 1H), 4.52 (t, J = 4.3 Hz, 1H), 4.59 (q, J = 7.0 Hz, 1H), 4.64 (d, J = 12.5 Hz, 1H), 5.13 (dd, J = 10. 2, 1.7 Hz, 1H), 5.31 (dd , J = 17.1,1.5 Hz, 1H), 5.70−5.78 (m, 1H), 5.86 (bs, 1H), 7.43 (dd, J = 9.3, 2.3 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.71-7.79 (m, 3H), 8.08 (dd, J = 8.2, 1.5 Hz, 1H), 8.34 (d, J = 9.5 Hz, 1H). LC-MS (retention) Time: 1.47), MS m / z 767 (M ⁺ +1).

Compound 121
Compound 121, N- {lS- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine- 1-carbonyl] -2,2-dimethyl-propyl} -oxalamic acid methyl ester (below)

Compound 121 was prepared using methyl oxalyl chloride. ¹ H NMR (MeOH) δ 1.02-1-1.12 (m, 3H), 1.07 (s, 9H), 1.23-1.26 (m, 2H), 1.45 (q, J = 5.5 Hz, 1H), 1.90 (q, J = 5.5 Hz, 1H), 2.25 (d, J = 8.9 Hz, 1H), 2.41−2.47 (m, 1H), 2.77 (dd, J = 13.9, 6.6 Hz, 1H), 2.92−2.97 (m, 1H), 3.79 (s, 3H), 4.07 (s, 3H), 4.16 (dd, J = 12.7, 2.9 Hz, 1H), 4.57−4.62 (m, 2H), 5.14 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 (dd, J = 17.1, 1.2 Hz, 1H), 5.72−5.77 (m, 1H), 5.86 (bs, 1H), 7.41 (dd, J = 9.3, 2.3 Hz, 1H), 7.54 (d , J = 2.4 Hz, 1H), 7.64 (s, H), 7.71-7.79 (m, 3H), 8.08 (dd, J = 8.2, 1.5 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H) ; LC-MS (retention time: 1.43), MS m / z 776 (M + + l)

Compound 122
Compound 122, {lS- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} -carbamic acid 2-fluoroethyl ester (below)

Compound 122 was prepared using 2-fluoroethyl chloroformate. ¹ H NMR (MeOH) δ 1.01-1.09 (m, 3H), 1.05 (s, 9H), 1.23-1.25 (m, 2H), 1.44 (q, J = 5.3 Hz, 1H), 1.89 (q, J = 5.5 Hz, 1H), 2.24 (q, J = 8.9 Hz, 1H), 2.40−2.46 (m, 1H), 2.77 (dd, J = 13.9, 6.9 Hz, 1H), 2.92−2.97 (m, 1H), 3.92 (dd, J = 5.7, 2.9 Hz, 0.5H), 3.95 (dd, J = 5.5, 2.8 Hz, 0.5H), 3.97 (dd, J = 5.5, 2.8 HZ, 0.5H), 4.01 (dd, J = 5.0, 2.6 Hz, 0.5H), 4.05 (s, 3H), 4.14 (dd, J = 12.2, 2.8 Hz, 1H) 4.24 (s, 1H), 4.36−4.38 (m, 1H), 4.45−4.48 ( m, 1H), 4.59−4.64 (m, 2H), 5.14 (dd, J = 10.4, 1.2 Hz, 1H), 5.30 (d, J = 17.1 Hz, 1H), 5.70−5.77 (m, 1H), 5.86 (bs, 1H), 7.42 (dd, J = 9.3, 2.3 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.64 (s, 1H), 7.71-7.78 (m, 3H), 8.09 ( d, J = 8.2 Hz, 2H), 8.33 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.46), MS m / z 780 (M ⁺ +1).

Compound 123
Compound 123, {1S- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} -carbamic acid vinyl ester (below)

Compound 123 was prepared using vinyl chloroformate. ¹ H NMR (MeOH) δ 1.05 (m, 9H), 1.01-1.13 (m, 3H), 1.24 (d, J = 2.4 Hz, 2H), 1.29 (bs, 1H), 1.44 (dd, J = 9.5, 5.5 Hz, 1H), 1.90 (dd, J = 8.1, 5.7 Hz, 1H), 2.24 (q, J = 8.6 Hz, 1H), 2.40−2.45 (m, 1H), 2.78 (dd, J = 13.6, 7.2 Hz, 1H), 2.92-2.97 (m, 1H), 4.06 (s, 3H), 4.11 (dd, J = 12.2, 2.8 Hz, 1H), 4.24 (d, J = 8.9 Hz, 1H), 4.32 (d , J = 5.5 Hz, 1H), 4.60−4.66 (m, 3H), 5.14 (d, J = 10.7 Hz, 1H), 5.31 (d, J = 17.1 Hz, 1H), 5.70−5.77 (m, 1H), 5.86 (bs, 1H), 6.68 (dd, J = 14.2, 6.3 Hz, 1H), 7.40 (dd, J = 9.5, 2.1 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.55 (s, 1H), 7.65 (s, 1H), 7.72-7.79 (m, 3H), 8.08 (d, J = 7.02 Hz, 1H), 8.30 (d, J = 9.5 Hz, 1H); LC-MS (Retention time: 1.56), MS m / z 760 (M ⁺ +1).

Compound 124
Compound 124, {lS- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} -carbamic acid prop-2-ynyl ester (below)

Compound 124 was prepared using propargyl chloroformate. ¹ H NMR (MeOH) δ 1.01-1.09 (m, 3H), 1.05 (s, 9H), 1.21-1.26 (m, 2H), 1.44 (dd, J = 9.5, 5.5 Hz, 1 H), 1.90 (dd , J = 7.9, 5.5 Hz, 1H), 2.24 (q, J = 8.9 Hz, 1H), 2.40−2.46 (m, 1H), 2.77 (dd, J = 14.2, 6.9 Hz, 1H), 2.83 (t, J = 2.1 Hz, 1H), 2.93−2.97 (m, 1H), 4.06 (s, 3H), 4.12 (dd, J = 12.2, 2.9 Hz, 1H), 4.22 (s, 1H), 4.33 (d, J = 2.4 Hz, 2H), 4.59−4.66 (m, 2H), 5.14 (dd, J = 10.4, 1.5 Hz, 1H), 5.30 (d, J = 17.4 Hz, 1H), 5.70−5.77 (m, 1H) , 5.86 (bs, 1H), 7.46 (dd, J = 9.2, 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.71-7.79 (m, 3H), 8.08 (dd, J = 7.0, 1.5 Hz, 2H), 8.37 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.49), MS m / z 772 (M ⁺ +1).

Compound 125
Compound 125, {lS- [2S- (lR-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} -carbamic acid 2,2-dimethyl-propyl ester (below)

Compound 125 was prepared using neopentyl chloroformate. ¹ H NMR (MeOH) δ 0.81 (s, 9H), 1.04 (s, 9H), 1.06-1.12 (m, 3H), 1.23-1.25 (m, 2H), 1.29 (s, 1H), 1.45 (dd, J = 9.5, 5.5 Hz, 1H), 1.91 (dd, J = 8.1, 5.5 Hz, 1H), 2.25 (q, Lu = 8.8,1H), 2.40−2.46 (m, 1H), 2.77 (dd, J = 14.4, 7.5 Hz, 1H), 2.93−2.98 (m, 1H), 3.17 (d, J = 10.1 Hz, 1H), 3.41 (d, J = 10.4 Hz, 1H), 4.05 (s, 3H ), 4.11 (dd, J = 12.4, 2.3 Hz, 1H), 4.21 (s, lH), 4.61−4.66 (m, 2H), 5.14 (dd, J = 10.4, 1.5 Hz, 1H), 5.31 (dd, J = 17.2, 1.1 Hz, 1H, 5.71−5.79 (m, 1H), 5.85 (bs, 1H), 7.40 (dd, J = 9.3, 2.0 Hz, 1H), 7.53 (d, J = 2.1, 1H), 7.65 (s, 1H), 7.71-7.79 (m, 3H), 8.08 (dd, J = 8.2, 1.5 Hz, 2H), 8.32 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.74 ), MS m / z 804 (M ⁺ +1).

Compound 126
Compound 126, {lS- [2S- (1R-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1- Carbonyl] -2,2-dimethyl-propyl} -carbamic acid allyl ester (below)

Compound 126 was prepared using allyl chloroformate. ¹ H NMR (MeOH) δ 1.05 (s, 9H), 1.06−1.09 (m, 4H), 1.22−1.25 (m, 2H), 1.44 (q, J = 5.5 Hz, 1H), 1.90 (q, J = 5.5 Hz, 1H), 2.25 (q, J = 8.9 Hz, lH), 2.40−2.46 (m, 1H), 2.78 (q, J = 14.0, 7 Hz, 1H), 2.92−2.97 (m, 1H), 4.05 (s, 3H), 4.10−4.15 (m, 1H), 4.21 (d, J = 5.5 Hz, 1H), 4.22 (s, 1H), 4.60−4.66 (m, 2H), 5.08 (dd, J = 10.5, 1.1 Hz, 1H), 5.14 (dd, J = 10.4, 1.2 Hz, 1H), 5.17 (dd, J = 17.1, 1.5 Hz, 1H), 5.31 (dd, J = 17.1, 1.2 Hz, 1H), 7.42 (dd, J = 9.5, 2.1 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.66 (s, 1H), 7.71-7.79 (m, 3H), 8.08 (dd, J = 6.9, 1.7 Hz, 2H), 8.33 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.56), MS m / z 774 (M ⁺ +1).

Compound 127
Compound 127, {1S- [2S- (1R-cyclopropanesulfonylaminocarbonyl-2S-vinyl-cyclopropylcarbamoyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-1-carbonyl ] -2,2-Dimethyl-propyl} -carbamic acid butyl ester (below)

Compound 127 was prepared using N-butyl chloroformate. ¹ H NMR (MeOH) δ 0.87 (t, J = 7.3 Hz, 3H), 1.04 (s, 9H), 1.07-1.11 (m, 2H), 1.23-1-1.31 (m, 4H), 1.40-1.46 (m, 3H), 1.90 (q, J = 5.5 Hz, 1H), 2.25 (q, J = 8.7 Hz, 1H), 2.40−2.46 (m, 1H), 2.77 (dd, J = 14.2, 6.9 Hz, 1H), 2.92−2.97 (m, 1H), 3.55−3.60 (m, 1H), 3.71−3.76 (m, 1H), 3.97 (s, 1H), 4.06 (s, 3H), 4.13 (dd, J = 12.2, 2.4 Hz, 1H), 4.21 (s, 1H), 4.60−4.66 (m, 2H), 5.13 (dd, J = 10.4, 2 Hz, 1H), 5.31 (d, J = 17.1 Hz), 1H), 5.70− 5.78 (m, 1H), 5.86 (bs, 1H), 7.41 (dd, J = 9.3, 2.0 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.72-7.79 (m, 3H), 8.07 (d, J = 7.0 Hz, 1H), 8.34 (d, J = 9.5 Hz, 1H); LC-MS (retention time: 1.68), MS m / z 790 (M ⁺ +1 ).

Example 39
Compound 128
Compound 128, 1- [3,3-dimethyl-2S- (2-nitrophenylamino) -butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid ( 1R-cyclopropanesulfonyl-aminocarbonyl-2S-vinylcyclopropyl) amide (below) was prepared as described in steps 39a-b below.

Step 39a: Preparation of 3,3-dimethyl-2S- (2-nitro-phenylamino) lacric acid (below)

To a slurry of L-tert-leucine (1.0 g, 7.7 mmol) in EtOH (anhydrous, 25 mL) in a pressurized medium flask was added 1-fluoro-2-nitrobenzene (812 pL, 7.7 mmol) and K ₂ CO ₃ (2.3 g, 15.4 mmol) was added. After heating at 105 ° C. for 2 hr, the resulting red reaction mixture was filtered to remove excess K ₂ CO ₃ and washed with DCM. The solvent was concentrated, the red paste was redissolved in DCM, neutralized with 1N HCl, and the aqueous layer was extracted with DCM. The DCM layers were washed with dried over MgSO _4, and concentrated. The red solid was redissolved in MeOH, concentrated to a slurry, and precipitated by adding Et ₂ O. A red solid product was obtained by vacuum filtration (1.6 g, 82% yield). ¹ H NMR (MeOH) δ 1.09 (s, 1H), 1.14 (s, 9H), 3.80 (s, 3H), 6.60 (ddd, J = 8.6, 7.0, 1.2 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 7.41 (ddd, J = 8.9, 7.0, 1.8 Hz, 1H), 8.11 (dd, J = 8.6, 1.5 Hz, 1H); LC-MS (retention time: 1.60), MS m / z 253 (M ⁺⁺ 1).

Step 39b: Preparation of Compound 128
To a solution of the product of step 27d (48.4 mg, 0.0745 mmol) in DMF (2 mL) is DIEA (65 μL, 0.372 mmol), HATU (57 mg, 0.149 mmol) and the product of step 39a (38.0 mg, 0.149 mmol). Added. After stirring at rt for 16 hr, the solvent was concentrated and the residue was purified by reverse phase preparative HPLC to give an orange solid as a TFA salt (22.1 mg, 32% yield). ¹ H NMR (MeOH) δ 1.07-1.10 (m, 2H), 1.13 (s, 9H), 1.21-1.30 (m, 2H), 1.42 (dd, J = 9.5, 5.5 Hz, 1H), 1.91 (dd, J = 8.2, 5.5 Hz, 1H), 2.24 (q, J = 8.7 Hz, 1H), 2.40−2.46 (m, 1H), 2.75 (dd, J = 13.9, 7.2 Hz, 1H), 2.94−2.99 (m , 1H), 4.08 (s, 3H), 4.12 (dd, J = 12.5, 2.4 Hz, 1H), 4.48 (d, J = 11.0 Hz, 1H), 4.67 (d, J = 7.6 Hz, 1H), 5.14 (dd, J = 10.7, 1.5 Hz, 1H), 5.30 (d, J = 17.1 Hz, 1H), 5.68 (m, 1H), 5.89 (br, s, 1H), 6.49 (t,
J = 7.8 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.91 (dd, J = 7.0, 1.5 Hz, 1H), 7.28 (dd, J = 9.3, 2.3 Hz, 1H), 7.48 ( d, J = 2.1 Hz, 1H), 7.60 (s, 1H), 7.73-7.79 (m, 3H), 7.96 (t, J = 9.5 Hz, 2H), 8.08 (d, J = 8.2 Hz, 1H); LC-MS (retention time: 1.67), MS m / z 811 (M ⁺ +1).

Example 40
Compound 129
Compound 129, 1- [3,3-dimethyl-2S- (3-nitropyridin-4-ylamino) -butyryl] -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S- Carboxylic acid (1R-cyclopropanesulfonylaminocarbonyl-2S-vinylcyclopropyl) amide (below) was prepared as described in steps s40a-b below.

Step 40a: Preparation of 3,3-dimethyl-2S- (3-nitro-pyridin-4-ylamino) -lacric acid potassium salt (below)

To a slurry of L-tert-leucine (3.0 g, 21.93 mmol) in EtOH (anhydrous, 75 mL) in a pressurized medium flask was added 4-methoxy-3-nitropyridine (3.38 g, 21.93 mmol) and K ₂ CO ₃ ( 6.7 g, 48.25 mmol) was added. After heating at 105 ° C. for 14 hr, the resulting yellow reaction mixture was filtered to remove excess K ₂ CO ₃ and washed with DCM. The solvent was concentrated and the resulting yellow paste was triturated with MeOH to a slurry and excess K ₂ CO ₃ was removed by filtration. The product was then dissolved in hot MeOH, concentrated to a slurry, and Et ₂ O was added to give a yellow green solid precipitate (4.95 g, 77% yield). ¹ H NMR (MeOH) δ 0.97 (s, 1H), 1.13 (s, 9H), 3.88 (s, 1H), 6.92 (d, J = 6.4 Hz, 1H), 8.15 (d, J = 6.4 Hz , 1H), 9.07 (s, 1H); LC-MS (retention time: 0.81), MS m / z 254 (M ⁺ +1).

Step 40a: Preparation of Compound 129 Compound 129 was prepared according to the method of Step 39b. ¹ H NMR (MeOH) δ 1.07-1.11 (m, 2H), 1.16 (s, 9H), 1.21-1.31 (m, 2H), 1.46 (dd, J = 9.5, 5.5 Hz, 1H), 1.91 (dd, J = 8.1, 5.6 Hz, 1H), 2.27 (q, J = 8.7 Hz, 1H), 2.45−2.50 (m 1H), 2.79 (dd, J = 14.4, 7.0 Hz, 1H), 2.94−2.99 (m, 1H), 4.04 (s, 3H), 4.25 (dd, J = 12.7, 3.2 Hz, 1H), 4.58 (d, J = 11.3 Hz, 1H), 4.71 (dd, J = 10.4, 7.3 Hz, 1H), 4.80 (s, 1H), 5.14 (d, J = 10.4 Hz, 1H), 5.31 (d, J = 17.1 Hz, 1H), 5.71−5.78 m, 1H), 5.95 (bs, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.32 (dd, J = 9.5, 2.1 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.71-7.79 (m, 3H), 7.99 (d, J = 7.0 Hz, 1H), 8.10 (d, J = 7.0 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 9.22 (s, 1H); LC-MS (retention time: 1.36), MS m / z 812 (M ⁺ +1).

Example 41
Compounds 130 and 131
Compounds 130 and 131, specifically 1- {3,3-dimethyl-2S- [methyl- (2-nitro-benzenesulfonyl) -amino] -butyryl} -4R- (7-methoxy-2-phenyl- The P3 isomer of quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropanesulfonyl-aminocarbonyl-2S-vinyl-cyclopropyl) amide was prepared as described in Steps 41a-d below. .

Step 41a: Preparation of 3,3-dimethyl-2S- (2-nitro-benzenesulfonylamino) lactic acid methyl ester (below)

To a solution of 1-(+)-methyl tert-leucineate hydrochloride (2.5 g, 13.8 mmol) in DCM (50 mL) was added DIEA (7.2 mL, 41.4 mmol) and 2-nitrobenzenesulfonyl chloride (3.5 g, 15.2 mmol). Was added. After stirring at rt for 24 hr, the reaction mixture was washed with 1N HCl (20 mmL) and extracted with DCM (25 mL). The combined DCM layers were washed with H ₂ 0 (10 mL) and neutralized with 1N NaOH. It was then dried over MgSO ₄ , concentrated and precipitated by adding Et ₂ O to give a yellow solid product (3.05 g, 67% yield). ¹ H NMR (MeOH) δ 0.98 (s, 9H), 3.38 (s, 3H), 3.79 (s, 1H), 7.77−7.83 (m, 2H), 7.84−7.86 (m, 1H), 8.04−8.05 ( m, 1H); LC-MS ( retention time: 1.39), MS m / z 353 (M + + l + Na).

Step 41b: Preparation of 3,3-dimethyl-2S- [methyl- (2-nitro-benzenesulfonyl) -amino] -lactic acid methyl ester

To a solution of 3,3-dimethyl-2S-[(2-nitrobenzenesulfonyl) -amino] -lactic acid methyl ester (505 mg, 1.53 mmol) in DMF (10 mL) was added K ₂ CO ₃ (423 mg, 3.06 mmol). ) Was added. After stirring at rt for 20 min, iodomethane (476 μL, 7.65 mmol) was added dropwise, and stirring was continued at rt. After 2 hr, excess K ₂ CO ₃ was removed by vacuum filtration and washed with MeOH. The solvent was concentrated and the resulting paste was redissolved in DCM (30 mL) and washed with H ₂ 0 (3 mL). The aqueous layer was extracted with DCM 2 x 25 mL. The combined DCM was washed with brine, dried over MgSO ₄ and concentrated to give a yellow solid (484 mg, 92% yield). ¹ H NMR (MeOH) δ 1.11 (s, 9H), 3.10 (s, 3H), 3.49 (s, 3H), 4.44 (s, 1H), 7.73 (dd, J = 7. 6, 1.8 Hz, 1H) , 7.77-7.83 (m, 2H), 8.02 (dd, J = 7.3, 1.8 Hz, 1H); LC-MS (retention time: 1.49), MS m / z 345 (M ⁺ +1).

Step 41c: 3,3-Dimethyl-2S- [methyl (2-nitro-benzenesulfonyl) -amino] Preparation of lactic acid (below)

THF / MeOH (1: 1) (4mL) of the product of Step 41b (250 mmg, 0.73 mmol) to a solution of, H ₂ 0 ₍₂ mL) Medium LiOH (122 mg, 2.90 mmol) was added. After stirring at rt for 24 hr, the solvent was concentrated, diluted with H ₂ 0 (5 mL), and diluted with DCM 2 × 20 mL. The DCM layer was dried over MgSO ₄ and concentrated to give a brown viscous starting material (72 mg). The aqueous layer was acidified with concentrated HCl (−pH 3) and extracted with 3 × 20 ml DCM. The combined DCM layer was dried over MgSO _4, concentrated, pale yellow solid product (140 mg, 82% yield based on recovered starting material (72 mg, 29%)) . 1 H NMR (MeOH) δ 1.14 (s, 9H), 3.12 (s, 3H), 4.43 (s, 1H), 7.71 (dd, J = 7. 63, 1.52 Hz, 1H), 7.74−7.78 (m, 2H), 8.03 (dd , J = 7.32, 1.83 Hz, 1H); LC-MS (retention time: 1.33), MS m / z 331 (M ⁺ +1).

Step 41d: Preparation of compounds 130 and 131 (below)

To a solution of the product of step 41c (44.1 mg, 0.133 mmol) in DCM (2 mL) was added oxalyl chloride (59 μL, 0.67 mmol) and DMF (1 μL). After stirring at rt for 0.5 hr, the solvent was concentrated, and the resulting acid chloride residue was dried under vacuum for 0.5 hr and used crude in the next reaction. The crude acid chloride was then added to the product of step 29a (107 mg, 0.133 mmol) and phosphagene base P1-tert-butyl-tris (tetramethylene) (249 pL, 1.33 mmol, Fluka) in DMF (1 mL). Treated with solution. After stirring at rt for 14 hr, the reaction mixture was diluted with DCM (20 mL) and washed with 1N HCl (3 mL). The aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated. The obtained residue was purified by reverse phase HPLC to obtain a first isomer (16.2 mg, 12% yield) and a second isomer (11.4 mg, 9% yield).

¹Ｈ ＮＭＲ(MeOH) δ 0.97−1.01 (m, 3H), 1.03 (s, 9H), 1.04 (s, 2H), 1.13−1.16 (m, 2H), 1.44 (dd, J = 9.5, 5.2 Hz, 1H), 1.93 (dd, J = 7.9, 5.5 Hz, 1H), 2.27 (q, J = 8.7 Hz, 1H), 2.45−2.51 m, 1H), 2.80 (dd, J = 14.3, 7.3 Hz, 1H), 2.83−2.88 (m, 1H), 3.16 (s, 3H), 3.97 (s, 1H), 4.06 (s, 3H), 4.21 (dd, J = 12.5, 3.7 Hz, 1H), 4.38 (d, J = 12.5 Hz, 1H), 4.60 (dd, J = 9.3, 7.5 Hz, 1H), 4.75 (s, 1H), 5.13 (dd, J = 10.7, 1.8 Hz, 1H), 5.31 (dd, J = 17.1, 1.2 Hz, 1H), 5.70−5.78 (m, 1), 5.89 (bs, 1H), 7.46 (dd, J = 9.5, 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 7.70−7.81 (m, 6H), 7.89 (dd, J = 8.6, 0.9 Hz, 1H), 7.92−7.95 (m, 1H), 8.07 (dd, J = 8.2−1.2 Hz, 2H), 8.19 (d, J = 9.2 Hz, 1H), ＬＣ−ＭＳ(保持時間: 1.39), ＭＳ m/z 890 (M⁺+1). The first isomer (below) is Compound 130 and the analytical data is shown below:

¹ H NMR (MeOH) δ 0.97-1.01 (m, 3H), 1.03 (s, 9H), 1.04 (s, 2H), 1.13-1.16 (m, 2H), 1.44 (dd, J = 9.5, 5.2 Hz, 1H), 1.93 (dd, J = 7.9, 5.5 Hz, 1H), 2.27 (q, J = 8.7 Hz, 1H), 2.45−2.51 m, 1H), 2.80 (dd, J = 14.3, 7.3 Hz, 1H) , 2.83−2.88 (m, 1H), 3.16 (s, 3H), 3.97 (s, 1H), 4.06 (s, 3H), 4.21 (dd, J = 12.5, 3.7 Hz, 1H), 4.38 (d, J = 12.5 Hz, 1H), 4.60 (dd, J = 9.3, 7.5 Hz, 1H), 4.75 (s, 1H), 5.13 (dd, J = 10.7, 1.8 Hz, 1H), 5.31 (dd, J = 17.1, 1.2 Hz, 1H), 5.70−5.78 (m, 1), 5.89 (bs, 1H), 7.46 (dd, J = 9.5, 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.65 ( s, 1H), 7.70−7.81 (m, 6H), 7.89 (dd, J = 8.6, 0.9 Hz, 1H), 7.92−7.95 (m, 1H), 8.07 (dd, J = 8.2−1.2 Hz, 2H) , 8.19 (d, J = 9.2 Hz, 1H), LC-MS (retention time: 1.39), MS m / z 890 (M ⁺ +1).

¹Ｈ ＮＭＲ: (MeOH) δ 1.01 (s, 9H), 1.03−1.08 (m, 2H), 1.19−1.24 (m, 2H), 1.54 (dd, J = 9.5, 5.5 Hz, 1H), 1.81−1.86 (m, 2H), 1.92 (dd, J = 7.8, 5.6 Hz, 1H), 2.24−2.31 (m, 1H), 2.41−2.50 (m, 1H), 2.80 (dd, J = 13.9, 6.9 Hz, 1H), 2.90−2.95 (m, 1H), 3.08−3.17 (m, 2H), 3.11 (s, 3H), 3.97 (s, 1H), 4.04 (s, 3H), 4.06 (s, 1H), 4.12 ((dd, J = 12.2, 2.8 Hz, 1H), 4.40 (s, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.72 (dd, J = 10.5, 6.9 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 5.34 (d, J = 17. 1 Hz, 1H), 5.79−5.84 (m, 1H), 5.87 (bs, 1H), 7.39 (dd, J = 9.2, 2.4 Hz, 1H), 7.45−7.48 (m, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.65−7.69 (m, 3H), 7.70−7.80 (m, 6H), 8.06 (dd, J = 8.2, 1.2 Hz, 1H), 8.11 (dd, J = 8.2, 1.5 Hz, 2H), 8.24 (d, J = 9.5 Hz, 1H) ; ＬＣ−ＭＳ(保持時間: 1.65), ＭＳ m/z 890 (M⁺+1). The second isomer (below) is compound 131 and the analytical data is shown below:

¹ H NMR: (MeOH) δ 1.01 (s, 9H), 1.03-1.08 (m, 2H), 1.19-1.24 (m, 2H), 1.54 (dd, J = 9.5, 5.5 Hz, 1H), 1.81-1.86 (m, 2H), 1.92 (dd, J = 7.8, 5.6 Hz, 1H), 2.24−2.31 (m, 1H), 2.41−2.50 (m, 1H), 2.80 (dd, J = 13.9, 6.9 Hz, 1H ), 2.90−2.95 (m, 1H), 3.08−3.17 (m, 2H), 3.11 (s, 3H), 3.97 (s, 1H), 4.04 (s, 3H), 4.06 (s, 1H), 4.12 ( (dd, J = 12.2, 2.8 Hz, 1H), 4.40 (s, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.72 (dd, J = 10.5, 6.9 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 5.34 (d, J = 17.1 Hz, 1H), 5.79−5.84 (m, 1H), 5.87 (bs, 1H), 7.39 (dd, J = 9.2, 2.4 Hz, 1H ), 7.45−7.48 (m, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.65−7.69 (m, 3H), 7.70−7.80 (m, 6H), 8.06 (dd, J = 8.2, 1.2 Hz, 1H), 8.11 (dd , J = 8.2, 1.5 Hz, 2H), 8.24 (d, J = 9.5 Hz, 1H); LC-MS ( retention time: 1.65), MS m / z 890 (M + + 1).

Example 42
Compounds 132 and 133
Compounds 132 and 133, which are (3,3-dimethyl-2-methylamino-butyryl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclo Propanesulfonylaminocarbonyl-2S-vinyl-cyclo-propyl) amide 2S and 2RP3 isomers, prepared as follows.

The preparation of compound 132 is shown above. Specifically, 2-mercaptoethanol (3 drops) and DBU (5 drops) were added to a solution of compound 130 (13.9 mg, 0.016 mmol) in DMF (1 mL), and stirring was started at rt. After 24 hr, the solvent was concentrated and purified by reverse phase HPLC to give a white solid product as the bis-TFA salt (7.2 mg, 48% yield). ¹ H NMR (MeOH) δ 0.86−0.91 (m, 1H), 1.07-1.14 (m, 3H), 1.16 (s, 9H), 1.19−1.22 (m, 1H), 1.25−1.33 (m, 4), 1.42 (dd, J = 9.5, 5.5 Hz, 1H), 1.92 (dd, J = 8.1, 5.7 Hz, 1H), 2.27 (q, J = 8.7 Hz, 1H), 2.41−2.47 (m, 1H), 2.54 (s, 3H), 2.79−2.84 (m, 1H), 2.93−2.97 (m, 1H), 4.03 (s, 3H), 4.13 (dd, J = 12.2, 3.1 Hz, 1H), 4.47 (d, J = 12.2 Hz, 1H), 4.76 (dd, J = 9.3, 7.5 Hz, 1H), 5.15 (dd, J = 10.4, 1.5 Hz, 1H), 5.30 (dd, J = 17.4 Hz, 1H), 5.68−5.75 (m, 1H), 5.86 (bs, 1H), 7.37 (dd, J = 9.2, 2.1 Hz, 1H), 7.52 (bs, 1H), 7.56 (s, 1H), 7.65-7.70 (m, 3H), 8.05-8.09 (m, 2H), 8.13 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.18), MS m / z 704 (M ⁺ +1).

¹Ｈ ＮＭＲ(MeOH) δ 0.86−0.93 (m, 1H), 1.09 (s, 9H), 1.15−1.23 (m, 4H), 1.27−1.33 (m, 3H), 1.37−1.45 (m, 3H), 1.92 (dd, J = 7.9, 5.5 Hz, 1H), 2.32 (q, J = 8.7 Hz, 1H), 2.49−2.57 (m, 1H), 2.75 (s, 3H), 2.86 (dd, J = 14.0, 7.6 Hz, 1H), 2.95−3.00 (m, 1H), 3.38−3.49 (m, 1H), 4.04 (s, 3H), 4.15 (s, 1H), 4.29 (dd, J = 12.5, 3.1 Hz, 1H), 4.39 (d, J = 12.2 Hz, 1H), 4.75 (t, J = 8.2 Hz, 1H), 5.16 (dd, J = 10.4, 1.2 Hz, lH), 5.34 (d, J = 17.1 Hz, 1H), 5.70−5.77 m, 1H), 5.97 (bs, 1H), 7.44 (dd, J = 9.5, 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.69−7.76 (m, 3H), 8.09 (dd, J = 7.0, 0.9 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H);ＬＣ−ＭＳ(保持時間: 1.21), ＭＳ m/z 704 (M⁺+1); Compound 133 (below) was prepared using Compound 131 by the method for preparing Compound 132.

¹ H NMR (MeOH) δ 0.86−0.93 (m, 1H), 1.09 (s, 9H), 1.15−1.23 (m, 4H), 1.27−1.33 (m, 3H), 1.37−1.45 (m, 3H), 1.92 (dd, J = 7.9, 5.5 Hz, 1H), 2.32 (q, J = 8.7 Hz, 1H), 2.49−2.57 (m, 1H), 2.75 (s, 3H), 2.86 (dd, J = 14.0, 7.6 Hz, 1H), 2.95−3.00 (m, 1H), 3.38−3.49 (m, 1H), 4.04 (s, 3H), 4.15 (s, 1H), 4.29 (dd, J = 12.5, 3.1 Hz, 1H ), 4.39 (d, J = 12.2 Hz, 1H), 4.75 (t, J = 8.2 Hz, 1H), 5.16 (dd, J = 10.4, 1.2 Hz, lH), 5.34 (d, J = 17.1 Hz, 1H) ), 5.70−5.77 m, 1H), 5.97 (bs, 1H), 7.44 (dd, J = 9.5, 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.69−7.76 (m, 3H), 8.09 (dd, J = 7.0, 0.9 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.21), MS m / z 704 (M ⁺ +1);

Example 43
Compound 134
Compound 134, 1- (2R-dimethylamino-3-phenylpropionyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (lR-cyclopropane-sulfonylaminocarbonyl) -2S-vinyl-cyclopropyl) amide (below) was prepared as follows.

4R- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2S-carboxylic acid (lR-cyclo-propanesulfonylaminocarbonyl-2S-vinylcyclopropyl) amide dihydrochloride (49.5 mg) in DCM (2 mL) , 0.061 mmol) was added DIEA (64 μL, 0.37 mmol), HATU (28. Omg, 0.074 mmol) and N, N-dimethyl-1-phenyl-alanine (14.Omg, 0.061 mmol). After stirring at rt for 0.5 hr, the solvent and excess DIEA were concentrated, and the resulting residue was purified by reverse phase preparative HPLC to give white solid compound 134 as a bis-TFA salt (14.Omg, 23% yield). Ratio), a yellow solid compound 135 was obtained as a bis-TFA salt (6.1 mg, 10% yield). ¹ H NMR (MeOH Compound 134) δ 1.12-1.16 (m, 2H), 1.20-1.25 (m, 1H), 1.28-1.33 (m, 1H), 1.42 (dd, J = 9.5, 5.2 Hz, 1H), 1.98 (dd, J = 7.9, 5.2 Hz, 1H), 2.26−2.31 (m, 2H), 2.64 (dd, J = 12.8, 8.1 Hz, lH), 3.01 (bs, 6H), 3.05−3.09 (m, 2H), 3.42 (dd, J = 13.4, 3.7 Hz, 1H), 4.03 (s, 3H), 4.08 (s, 1H), 4.48 (dd, J = 10.1, 4.0 Hz, 1H), 4.58 (dd, J = 9.8, 7.0 Hz, 1H), 5.17 (dd, J = 10.4, 1.5 Hz, 1H), 5.33 (d, J = 17.4 Hz, 1H), 5.60 (bs, 1H), 5.76−5.81 (m, 1H) , 7.32−7.35 (m, 2H), 7.36−7.40 (m, 4H), 7.42 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.67−7.71 (m, 4H ), 8.02-8.04 (m, 2H), 8.13 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.37), MS m / z 752 (M ⁺ +1).

¹Ｈ ＮＭＲ(MeOH) δ 1.10−1.22 (m, 2H), 1.21−1.28 (m, 1H), 1.29−1.35 (m, 1H), 1.42 (dd, J = 9.5, 5.2 Hz, 1H), 1.97 (dd, J = 8.2, 5.2 Hz, 1H), 2.28−2.36 (m 2H), 2.58−2.36 (m, 2H), 3.03 (s, 6H), 3.06−3.08 (m, 3H), 3.39 (dd, J = 12.5, 4.0 Hz, 1H), 4.04 (s, 3H), 4.08 (s, 1H), 4.11 (d, J = 12.8 Hz, 1H), 4.51 (dd, J = 10.7, 4.0 Hz, 1H), 4.62 (dd, J = 9.8, 7.0 Hz, 1H), 5.16 (dd, J = 10.2, 1.7 Hz, 1H), 5.34 (dd, J = 16.8, 1.5 Hz, 1H), 5.63 (bs, 1H), 5.75−5.83 (m, 1H), 7.33 (dd, J = 6.1, 2.4 Hz, 1H), 7.38−7.42 (m, 5H), 7.47 (s, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.69−7.76 (m, 4H), 8.02−8.02 (m, 2H), 8.18 (d, J = 9.2 Hz, 1H);ＬＣ−ＭＳ(保持時間: 1.30), ＭＳ m/z 752 (M⁺+l) ; Example 44
Compound 135
Compound 135, 1- (2S-dimethylamino-3-phenylpropionyl) -4R- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2S-carboxylic acid (1R-cyclopropanesulfonylamino-carbonyl) -2S-vinylcyclopropyl) amide (below) was prepared by the method of Example 43.

¹ H NMR (MeOH) δ 1.10-1.22 (m, 2H), 1.21-1.28 (m, 1H), 1.29-1.35 (m, 1H), 1.42 (dd, J = 9.5, 5.2 Hz, 1H), 1.97 ( dd, J = 8.2, 5.2 Hz, 1H), 2.28−2.36 (m 2H), 2.58−2.36 (m, 2H), 3.03 (s, 6H), 3.06−3.08 (m, 3H), 3.39 (dd, J = 12.5, 4.0 Hz, 1H), 4.04 (s, 3H), 4.08 (s, 1H), 4.11 (d, J = 12.8 Hz, 1H), 4.51 (dd, J = 10.7, 4.0 Hz, 1H), 4.62 (dd, J = 9.8, 7.0 Hz, 1H), 5.16 (dd, J = 10.2, 1.7 Hz, 1H), 5.34 (dd, J = 16.8, 1.5 Hz, 1H), 5.63 (bs, 1H), 5.75− 5.83 (m, 1H), 7.33 (dd, J = 6.1, 2.4 Hz, 1H), 7.38−7.42 (m, 5H), 7.47 (s, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.69 −7.76 (m, 4H), 8.02−8.02 (m, 2H), 8.18 (d, J = 9.2 Hz, 1H); LC-MS (retention time: 1.30), MS m / z 752 (M ⁺ + l) ;

Example 45
1-Amino-spiro [2.3] hexane-1-carboxylic acid methyl ester hydrochloride (below) was prepared in steps 45a-45c as described below.

Step 45a: [2.3] Production of hexane-1,1-dicarboxylic acid dimethyl ester (below)

To a mixture of methylene-cyclobutane (1.5 g, 22 mmol) and Rh ₂ (OAc) ₄ (125 mg, 0.27 mmol) in anhydrous CH ₂ Cl ₂ (15 mL) was added dimethyldiazomalonate (J. Lee et al., Synth Comm., 1995, 25, 1511-1515) 3.2 g (20 mmol) was added at 0 ° C. over 6 h. The reaction mixture was then warmed to rt and stirred for an additional 2 h. The mixture was concentrated and purified by flash chromatography (eluting with 10: 1 hexane / Et ₂ O to 5: 1 hexane / Et ₂₀ ) and 3.2 g (72%) of [2.3] hexane--as a yellow oil. 1,1-dicarboxylic acid dimethyl ester was obtained. ¹ H NMR (300 MHz, CDC1 ₃ ) δ 3.78 (s, 6 H), 2.36 (m, 2 H), 2.09 (m, 3 H), 1.90 (m, 1 H), 1.67 (s, 2 H) LC-MS: MS m / z 199 (M ⁺ +1) (Method D).

Step 45b: Production of spiro [2.3] hexane-1,1-dicarboxylic acid methyl ester (below)

To a mixture of spiro [2.3] hexane-1,1-dicarboxylic acid dimethyl ester 1 (200 mg, 1.0 mmol) in 2 mL of MeOH and 0.5 mL of water was added KOH (78 mg, 1.4 mmol). This solution was stirred at rt for 2 days. It was then acidified with dilute HCl and extracted twice with ether. Dry the organic layers were washed with (MgSO _4), concentrated to give 2 135 mg (73%) as a white solid. ¹ H NMR (300 MHz, CDC1 ₃ ) δ 3.78 (s, 3 H), 2.36-1.90 (m, 8 H). LC-MS: MS m / z 185 (M ⁺ +1) (Method D).

Step 45c: Preparation of the title compound, amino-spiro [2.3] hexane-1-carboxylic acid methyl ester hydrochloride Spiro [2.3] hexane-1,1-dicarboxylic acid methyl ester in 3 mL of anhydrous t-BuOH 2 To a mixture of (660 mg, 3.58 mmol), DPPA 1.08 g (3.92 mmol) and Et ₃ N 440 mg (4.35 mmol) were added. The mixture was 21 h heating under reflux, then it was partitioned between H ₂ 0 and ether. The ether layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. To this oil was added 3 mL of 4 M HCl / dioxane solution. The acidic solution was stirred at rt for 2 h and then concentrated in vacuo. The residue was triturated with ether to give 400 mg (58%) of 3 as a white solid.
¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.96 (br s, 3 H), 3.71 (s, 3 H), 2.41 (m, 1 H), 2.12 (m, 4 H), 1.93 (m, 1 H), 1.56 (q, 2 H, J = 8 Hz). MS of free amine: MS m / z 156 (M ⁺ +1) (Method D).

Example 46
Compound 136
Compound 136, {1- [2- (1-cyclopropanesulfonyl-aminocarbonyl-spiro [2.3] hex-1-ylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -Pyrrolidine-1-carbonyl] -2,2-dimethyl-propyl} -carbamic acid tert-butyl ester (below) was prepared as described in steps 46a-c.

Step 46a: 1-{[1- (2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl Production of] -amino} -spiro [2.3] hexane-1-carboxylic acid methyl ester (below)

1- (2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carboxylic acid in CH ₂ Cl ₂ ( 50 mg, 0.087 mmol), iPr ₂ EtN (56 mg, 0.43 mmol), then HBTU (40 mg, O. 10 mmol), HOBT-H ₂ 0 (16 mg, 0.10 mmol) and 1-amino- Spiro [2.3] -carboxylic acid methyl ester hydrochloride (18 mg, 0.094 mmol) was added. Stir at rt overnight. The reaction mixture was diluted with EtOAc, washed with saturated aq. NaHCO _3, washed with brine, dried over MgSO _4, filtered, and concentrated in vacuo. The residue was flash chromatographed eluting with 1: 1 hexane / EtOAc to give the title product (60 mg, 96%) as a white solid. LC-MS: (retention time 1.74 min), MS m / z 715 (M ⁺ +1) (Method D).

Step 46b: 1-{[1- (2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl Production of] -amino} -spiro [2.3] hexane-1-carboxylic acid (below)

1-{[1- (2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl) -4- (7-methoxy-2-phenyl-quinoline) in THF 3 mL, MeOH 1.5 mL and H ₂ 0 0.4 mL To a mixture of -4-yloxy) -pyrrolidine-2-carbonyl] -amino} -spiro [2.3] hexane-1-carboxylic acid methyl ester (60 mg, 0.084 mmol), LiOH (30 mg, 1.5 mmol) was added. Added. The mixture was stirred at rt for 3 days. It was then concentrated and partitioned between saturated aqueous NaHCO ₃ and ether. The aqueous layer was acidified with dilute HCl to pH = 4 and extracted three times with EtOAc. The combined EtOAc extracts were dried over magnesium sulfate, filtered, concentrated and 55 mg of 1-{[1- (2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl) -4- (7 -Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -spiro [2.3] hexane-1-carboxylic acid was obtained as a white solid (93%). LC-MS: (retention time 1.71 min), MS m / z 701 (M ⁺ +1) (Method D).

Step 46c: Compound 136
To a mixture of CDI (17 mg, 0.10 mmol) in THF (3 mL) was added 1-{[1- (2-tert-butoxycarbonylamino-3,3-dimethylbutyryl) -4- (7-methoxy-2- Phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -spiro [2.3] -hexane-1-carboxylic acid (55 mg, 0.078 mmol) was added. The mixture was heated to reflux for 1 h and allowed to cool to rt. Cyclopropylsulfonamide (13 mg, 0.10 mmol) was added followed by DBU (16 mg, 0.10 mmol). The mixture was stirred at rt for 24 h and then diluted with EtOAc. The solution was washed with pH = 4 buffer, saturated aqueous NaHCO ₃ solution and brine, dried over MgSO ₄ , filtered and concentrated. The residue was prep TLC, eluting three times with CH ₂ C1 ₂ in 2.5% MeOH, 13 mg of Compound 148, {1- [2- (1-cyclopropane sulfonylaminocarbonyl - spiro [2.3] hex - 1-ylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) pyrrolidine-1-carbonyl] -2,2-dimethyl-propyl} -carbamic acid tert-butyl ester as a white solid (20%). LC-MS: (retention time 1.63 min), MS m / z 804 (Method D).

ＬＣ−ＭＳ: (保持時間 1.62 min), ＭＳ m/z 804 (方法D). Example 47
The following compound was also prepared according to the method of Example 46 using the product of step 45c.
Compound 137

LC-MS: (retention time 1.62 min), MS m / z 804 (Method D).

ＬＣ−ＭＳ: (保持時間 1.56 min), ＭＳ m/z 790 (方法D). Compound 138

LC-MS: (retention time 1.56 min), MS m / z 790 (Method D).

Example 48
Compound 139
Compound 139, [1- [2- (1-Cyclopropanesulfonylaminocarbonyl-spiro [2.4] hept-1-ylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy)- Pyrrolidine-1-carbonyl] -2,2-dimethyl-propyl} carbamic acid tert-butyl ester (below) was prepared as described in steps 48a-d.

工程４５aの方法を用いて、メチレンシクロペンタン1.14g(13.9 mmol)およびジメチルジアゾマロネート2.0 g(12.6 mmol)を反応させ、ジメチルエステル1.8 gを得た(67%)。¹Ｈ ＮＭＲ(300 MHz, CDC1₃) δ 3.73 (s, 6 H), 1.80 (m, 2 H), 1.70 (m, 4 H), 1.60 (m, 4 H). ＬＣ−ＭＳ: ＭＳ m/z 213 (M⁺+1)(方法D). Step 48a: Spiro [2.4] heptane-1,1-dicarboxylic acid dimethyl ester (below) was prepared as follows.

Using the method of step 45a, 1.14 g (13.9 mmol) of methylenecyclopentane and 2.0 g (12.6 mmol) of dimethyl diazomalonate were reacted to give 1.8 g of dimethyl ester (67%). ¹ H NMR (300 MHz, CDC1 ₃ ) δ 3.73 (s, 6 H), 1.80 (m, 2 H), 1.70 (m, 4 H), 1.60 (m, 4 H). LC-MS: MS m / z 213 (M ⁺ +1) (Method D).

Step 48b: Spiro [2.4] heptane-1,1-dicarboxylic acid methyl ester (below) was prepared as follows.

Using the method of step 45b, 1.7 g (8.0 mmol) of the product of step 48a and 493 mg (8.8 mmol) of KOH to spiro [2.4] heptane-1,1-dicarboxylic acid methyl ester 1.5 g (94%) Got. ¹ H NMR (300 MHz, CDC1 ₃ ) δ 3.80 (s, 3 H), 2.06 (d, 1 H, J = 5 Hz), 1.99 (d, 1 H, J = 5 Hz), 1.80−1.66 (m LC-MS: MS m / z 199 (M ⁺ +1) (Method D).

Step 48c: 1-amino-spiro [2.4] heptane-1-carboxylic acid methyl ester hydrochloride (below) was prepared as follows.

Using the method of step 45c, the hydrochloride salt 180 mg (35%) was obtained from step 48b product 500 mg (2.5 mmol), DPPA 705 mg (2.5 mmol) and Et ₃ N 255 mg (2.5 mmol). . ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.90 (br s, 3 H), 3.74 (s, 3 H), 1.84 (m, 1 H), 1.69 (m, 4 H), 1.58 (m, 4 H), 1.46 (d, 1 H, J = 6 Hz). LC-MS of the free amine: MS m / z 170 (M ⁺ +1) (Method D).

  Step 48d: Compound 139 was prepared according to the method of Example 46 using the product of Step 48c. Retention time (min.) 1.69 MS data (M + 1) m / z 818 (Method D).

Example 49
Compound 140
Compound 140, {1- [2- (1-cyclopropanesulfonylaminocarbonyl-spiro [2.2] pentan-1-ylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy)- Pyrrolidine-1-carbonyl] -2,2-dimethyl-propyl} -carbamic acid tert-butyl ester (below) was prepared as described in steps 49a-d.

Step 49a: Spiro [2.2] pentane-1,1-dicarboxylic acid dimethyl ester (below) was prepared as follows.

Anhydrous CH ₂ C1 ₂ (10 mL) in methylene cyclopropane (1.0 g, 18.5 mmol) ( P. Binger, US Patent prepared as described in Serial No. 5,723,714) and Rh ₂ (OAc) ₄ in (82mg, 0.185 mmol) To the mixture was added dimethyldiazomalonate (2.9 g, 18.3 mmol) at 0 ° C. A cooled finger-like protrusion was placed on the top of the flask, and the temperature was maintained at -10 ° C. The reaction mixture was warmed to rt and stirred for an additional 2 h. The mixture was concentrated in vacuo, was purified by flash chromatography (10: 1 hexane / Et ₂ O~5 eluting 1 hexane / Et ₂ O), to give a yellow oil dimethyl ester 0.85 g (25%) . ¹ H NMR (300 MHz, CDC1 ₃ ) δ 3.73 (s, 6 H), 1. 92 (s, 2 H), 1.04 (d, 4 H, J = 3 Hz).

工程４５bの方法を用いて、工程４９aの生成物800 mg(4.3 mmol)およびKOH 240 mg(4.3 mmol)からスピロ[２.２]ペンタン−１,１−ジカルボン酸メチルエステル600 mg(82%)を得た。¹Ｈ ＮＭＲ(300 MHz, CDC1₃) δ 3.82 (s, 6 H), 2.35 (d, 1 H, J=3 Hz), 2.26 (d, 1 H, J=3 Hz), 1.20 (m, 1 H), 1.15 (m, 1 H), 1.11 (m, 1 H), 1.05 (m, 1 H). ＬＲＭＳ: ＭＳ m/z 169 (M⁺−1)(方法D). Step 49b: Spiro [2.2] pentane-1,1-dicarboxylic acid methyl ester (below) was prepared as follows.

Using the method of step 45b, the product of step 49a from 800 mg (4.3 mmol) and KOH 240 mg (4.3 mmol) to spiro [2.2] pentane-1,1-dicarboxylic acid methyl ester 600 mg (82%) Got. ¹ H NMR (300 MHz, CDC1 ₃ ) δ 3.82 (s, 6 H), 2.35 (d, 1 H, J = 3 Hz), 2.26 (d, 1 H, J = 3 Hz), 1.20 (m, 1 H), 1.15 (m, 1 H), 1.11 (m, 1 H), 1.05 (m, 1 H). LRMS: MS m / z 169 (M ⁺ −1) (Method D).

Step 49c: 1-amino-spiro [2.2] pentane-1-carboxylic acid methyl ester hydrochloride (below) was prepared as follows.

Using the method of step 45c, the hydrochloride salt 82 mg (20%) was obtained from 400 mg (2.3 mmol) of the product of step 49b, DPPA 700 mg (2.5 mmol) and Et ₃ N 278 mg (2.7 mmol). ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.19 (br s, 3 H), 3.81 (s, 3 H), 2.16, (d, J = 5.5 Hz, 1 H), 2.01 (d, J = 5.5 Hz, 1 H), 1.49 (m, 1 H), 1.24, (m, 1 H), 1.12 (m, 2 H). LRMS of free amine: MS m / z 142 (M ⁺ +1) (Method D).

  Step 49d: Compound 140 was prepared according to the method of Example 46 using the product of Step 49c. Retention time (min.) 1.59 MS data (M + 1) m / z 790 (Method D).

Example 50
Compound 141
Compound 141, {1- [2- (1-cyclopropanesulfonylaminocarbonyl-spiro [2.2] pentan-1-ylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy)- Pyrrolidine-1-carbonyl] -2,2-dimethyl-propyl} -carbamic acid tert-butyl ester (below) was prepared as described in steps 50a-d.

Step 50a: 5-Amino-spiro [2.3] Hexane-5-carboxylic acid ethyl ester (below) was prepared as follows.

Spiro [bicyclopropylidene (A. Meijere et al., Org. Syn. 2000, 78, 142-151) was prepared as described in A. Meijere et al., J. Org. Chem. 1988, 53, 152-161 [ 2.3] Hexan-4-one 13 (500 mg, 5 mmol) was mixed with ammonium carbamate (1.17 g, 15 mmol) and potassium cyanide (812 mg, 12.5 mmol) in 50 mL EtOH and 50 mL water. The mixture was heated at 55 ° C. for 2 days. Then NaOH (7 g, 175 mmol) was added and the solution was heated to reflux overnight. The mixture was then cooled to 0 ° C., acidified with concentrated HCl to pH 1 and concentrated in vacuo. EtOH was added to the crude amino acid mixture, then evaporated to dryness (5x) to remove residual moisture. The residue dissolved in 100 mL of EtOH was cooled to 0 ° C. Was treated with SOC1 ₂ in 1 mL, it was refluxed for 3 days. The solid was collected by filtration, and the filtrate was concentrated in vacuo to give a crude product. The crude product was partitioned between 3N NaOH, NaCl and EtOAc. The organic phase was dried over potassium carbonate and concentrated. The residue was purified using column chromatography on C18 silica gel (eluting with MeOH / H ₂ 0) to give 180 mg (21%) of an oily 15. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20 (br s, 2 H), 4.27 (s, 2 H), 2.80 (s, 1 H), 2.54 (s, 1 H), 2.34 (m, 2 H ), 1.31 (s, 3 H), 1.02 (s, 1 H), 0.66 (m, 3 H). ¹³ C NMR (300 MHz, CDC1 ₃ ) δ 170.2 (s), 63.0 (s), 62.8 (s ), 26.1 (s), 26.0 (s), 24.9 (s), 13.9 (s), 11.4 (s), 10.9 (s) .LC-MS: MS m / z 170 (M ⁺ +1) (Method D ).

  Step 50d: Compound 141 was prepared according to the method of Example 46 using the product of Step 50c. Retention time (min.) 1.87 MS data (M + 1) m / z 804 (Method D).

塩、ＢOCＮＨ−Ｐ3(L−t−BuGly)−Ｐ2[(４Ｒ)(２−フェニル−７−メトキシキノリン−４−オキソ)−Ｓ−プロリン]−Ｐ1(1R,2SビニルＡcca)−ＢOCＮＨ−２−シクロプロパンメタンスルホン酸塩(下記)を下記のようにして製造した。 Example 51
Salt production

Salt, BOCNH-P3 (Lt-BuGly) -P2 [(4R) (2-phenyl-7-methoxyquinoline-4-oxo) -S-proline] -P1 (1R, 2S vinyl Acca) -BOCNH-2 -Cyclopropane methanesulfonate (below) was prepared as follows.

BOCNH-P3 (1-t-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline dissolved in 5 mL of CH ₂ Cl ₂ cooled to −78 ° C. ] -P1 (1R, 2S vinyl Acca) -CONHS0 ₂ - to a solution of cyclopropane 100 mg (0.124 mmol), was added methanesulfonic acid 8.4 L (0.13 mmol), the mixture was allowed to warm over 10 min until rt. The mixture was concentrated in vacuo, precipitated from the minimum amount of Et ₂ 0 in CH ₂ Cl _2, filtered, concentrated, BOCNH-P3 (L-t -BuGly) as a white solid -P2 [(4R) - ( 2-Phenyl-7-methoxyquinoline-4-oxo) -S-proline] -P1 (1R, 2S vinyl Acca) -BOCNH-2-cyclopropanemethanesulfonate 98 mg was obtained: LC-MS (retention time : 1.63, Method A), MS m / z 790 (M ⁺ +1). HRMS m / z (M + H) ⁺ C ₄₁ H ₅₂ N ₅ S0 ₉ : Calculated 790.3486, Found 790.3505.

塩、ＢOCＮＨ−Ｐ3(L−t−BuGly)−Ｐ2[(4R)−(２−フェニル−7−メトキシキノリン−４−オキソ)−Ｓ−プロリン]−Ｐ1(1R,2SビニルＡcca)−ＢOCＮＨ−２−シクロプロパン トリフルオロ酢酸塩(下記)を下記のようにして製造した。

BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline] -P1 (1R, 2S vinyl Acca) -BOCNH- 2-Cyclopropane trifluoroacetate (below) was prepared as follows.

-78 BOCNH-P3 (L-t -BuGly) dissolved in chilled CH ₂ Cl ₂ 5 mL in ℃ -P2 [(4R) - ( 2- phenyl-7-methoxyquinoline-4-oxo) -S- proline ] To a solution of 100 mg (0.124 mmol) of -P1 (1R, 2S vinyl Acca) -BOCNH-2-cyclopropane was added 10.7 μL (0.14 mmol) of TFA and the mixture was warmed to rt over 10 min. The mixture was concentrated in vacuo, precipitated from a minimum amount of CH ₂ Cl ₂ in Et ₂ 0, filtered and concentrated to give BOCNH-P 3 (Lt-BuGly) -P 2 [(4R)- (2-phenyl-7-methoxyquinoline-4-oxo) -S- proline] -P1 (1R, 2S vinyl Acca) -CONHS0 ₂ - was obtained mg cyclopropane trifluoroacetate 98.4: LC-MS (retention Time: 1.61, Method A), MS m / z 790 (M ⁺ +1). HRMS m / z (M + H) ⁺ C ₄₁ H ₅₂ N ₅ SO ₉ : Calculated 790.3486, Found 790.3505

塩、ＢOCＮＨ−Ｐ3(L−t−BuGly)−Ｐ2[(4R)−(２−フェニル−7−メトキシキノリン−４−オキソ)−Ｓ−プロリン]−Ｐ1(1R,2SビニルＡcca)−ＣＯＮＨＳ０₂−シクロプロパン塩酸塩(下記)を下記のようにして製造した。

Salt, BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline] -P1 (1R, 2S vinyl Acca) -CONHS0 ₂ -Cyclopropane hydrochloride (below) was prepared as follows.

BOCNH-P3 (Lt-BuGly) -P2 [(4R)-(2-phenyl-7-methoxyquinoline-4-oxo) -S-proline dissolved in 5 mL of CH ₂ Cl ₂ cooled to −78 ° C. ] -P1 (1R, 2S vinyl Acca) -CONHS0 ₂ - to a solution of cyclopropane 100 mg (0.124 mmol), was added 4N HCl in dioxane 47 μL (0.19 mmol), the mixture was warmed over 10 min to rt And then concentrated in vacuo. This process was repeated with a further 20 μl (0.08 mmol). The mixture was precipitated from Et ₂ 0 in minimum amount of CH ₂ Cl _2, filtered, and concentrated to a white solid, BOCNH-P3 (L-t -BuGly) -P2 [(4R) - (2- phenyl -7 -Methoxyquinoline-4-oxo) -S-proline] -P1 (1R, 2S vinyl Acca) -CONHSO ₂ -cyclopropane hydrochloride 94 mg was obtained: LC-MS (retention time: 1.66, method A), MS m / z 790 (M ⁺ +1). HRMS m / z (M + H) ⁺
C ₄₁ H ₅₂ N ₅ S0 ₉ : Calculated value 790.3486, Actual value 790.3495.

Example 52
Biological Study recombinant HCV NS3 / 4A-flop protease complex FRET peptide test The purpose of this in vitro study, the inhibition of the BMS according to the following with the compounds of the invention, H77C or derived from J416S strains the HCV NS3 protease complexes Is to measure. This test provides an indication of how effective the compounds of the invention are in inhibiting HCV visible proteolytic activity.

  Serum of HCV-infected patients was obtained from Dr. T. Wright of San Francisco Hospital. The designed full-length cDNA template of the HCV genome (BMS strain) was selected from DNA fragments obtained by reverse transcription-PCR (RT-PCR) of serum RNA based on homology between other genotype 1a strains. Were constructed using different primers. From the determination of the whole genome sequence, genotype 1a was designated as an HCV isolate by the classification of Simmonds et al. (P Simmonds, KA Rose, S Graham, SW Chan, F McOmish, BC Dow, EA Follett, PL Yap and H Marsden, J. Clin. Microbiol., 31 (6), 1439-1503 (1993)). The amino acid sequence of the nonstructural region, NS2-5B, was shown to be> 97% consistent with HCV genotype 1a (H77C) and 87% consistent with genotype 1b (J4L6S). Infected clones, H77C (1a genotype) and J4L6S (1b genotype) were obtained from R. PurcelL (NIH) and the sequences are published in the gene bank (AAB67036, Yanagi, M., Purcell, RH, Emerson , SU and Bukh, J. Proc. Natl. Acad. Sci. USA 94 (16), 8738-8743 (1997); AF054247, Yanagi, M., St Claire, M., Shapiro, M., Emerson, SU, Purcell, RH and Bukh, J, Virology 244 (1), 161-172. (1998)).

BMS, H77C and J4L6S strains were used for the production of recombinant NS3 / 4A protease complex. DNA encoding the recombinant HCV NS3 / 4A protease complex (from amino acids 1711) was prepared for these strains as described by P. Gallinari et al. (Gallinari P, Paolini C, Brennan D, Nardi C, Steinkuhler C, De Francesco R. Biochemistry, 38 (17): 5620-32, (1999)). In summary, a 3-lysine solubilizing end was added to the 3′-end of the NS4A coding region. The cysteine at position P1 of the NS4A-NS4B cleavage site (amino acid 1711) was changed to glycine to avoid proteolytic cleavage of the lysine tag. In addition, a serine mutation from cysteine was introduced into amino acid position 1454 by PCR to avoid autolytic cleavage of the NS3 helicase domain. The mutant DNA fragment was cloned into a pET21b bacterial expression vector and the NS3 / 4A complex was expressed in E. coli BL21 (DE3) with modifications to the same protocol as described by P. Gallinari et al. (Gallinari P, Brennan D, Nardi C, Brunetti M, Tomei L, Steinkuhler C, De Francesco R., J Virol. 72 (8): 6758-69 (1998)). In summary, NS3 / 4A expression was induced with 0.5 mM IPTG for 22 hours at 20 ° C. About 80 g of wet cell paste was obtained by normal fermentation (1OL). Cells were treated with 25 mM HEPES, pH 7.5, 20% glycerin, 500 mM NaCl, 0.5% Triton-X100, 1 μg / ml lysozyme, 5 mM MgCl ₂ , 1 μg / ml DNaseI, 5 mM β-mercaptoethanol (βME), protease inhibitor— Resuspended in lysis buffer (10 mL / g) containing no EDTA, homogenized, and incubated for 20 minutes at 4 ° C. The homogenate was sonicated and ultracentrifuged at 235000 g for 1 hr at 4 ° C. Imidazole was added to the supernatant to a final concentration of 15 mM, and the pH was adjusted to 8.0. The crude protein extract was loaded onto a Ni-NTA column pre-equilibrated with buffer B (25 mM HEPES, pH 8.0, 20% glycerin, 500 mM NaCl, 0.5% Triton-X100, 15 mM imidazole, 5 mM βME). The sample was filled at a flow rate of 1 mL / min. The column was washed with 15 column volumes of Buffer C (same as Buffer B except 0.2% Triton-X100). The protein was washed with 200 mM imidazole in 5 column volumes of buffer.

  NS3 / 4A protease complex-containing fractions were collected and desalted column Superdex pre-equilibrated with buffer D (25 mM HEPES, pH 7.5, 20% glycerin, 300 mM NaCl, 0.2% Triton-X100, lOmM βME) -Filled S200. The sample was filled at a flow rate of 1 mL / min. NS3 / 4A protease complex-containing fractions were collected and concentrated to about 0.5 mg / ml. The purity of NS3 / 4A protease complex derived from BMS, H77C and J4L6S strains was estimated to be 90% or higher by SDS-PAGE and mass spectrometry.

  The enzyme was stored at −80 ° C., thawed on ice, and diluted with test buffer before use. The substrate used for the NS3 / 4A protease test described in Taliani et al., Anal. Biochem. 240 (2): 60-67 (1996) was cleaved by the enzyme at the ester linkage. The sequence is loosely based on the NS4A / NS4B natural cleavage site. Peptide substrates were incubated with one of three of the recombinant NS3 / 4A complexes in the presence or absence of a compound of the invention and monitored in real time using the Cytofluor Series 4000.

The reagents were as follows: HEPES and glycerin (highest purity) were obtained from GIBCO-BRL. DMSO was obtained from Sigma. β-mercaptoethanol was obtained from Bio Rad.
Test buffer: 50 mM HEPES, pH 7.5; 0.15 M NaCl; 0.1% Triton; 15% glycerin; 10 mM βME.
Substrate: 2 mM final concentration (stored at −20 ° C. from 2 mM stock solution in DMSO).
HCV NS3 / 4A type 1a (lb), 2-3 nM final concentration (from 5 μM stock solution in 25 mM HEPES, pH 7.5, 20% glycerin, 300 mM NaCl, 0.2% Triton X100, lOmM βME).

The test was performed in a 96-well polystyrene plate manufactured by Falcon. Each well contained 25 μl NS3 / 4A protease complex in test buffer, 50 μl of the compound of the invention in 10% DMSO / test buffer and 25 μl substrate in test buffer. A control (no compound) was also prepared on the same test plate. The enzyme complex was mixed with the compound or control solution for 1 min and the substrate was added to start the enzyme reaction. The test plate was read immediately using a Cytofluor Series 4000 (Perspective Biosystems). The instrument was set to read 340 nm emission and 490 nm excitation at 25 ° C. The reaction was generally performed for about 15 minutes.
The percent inhibition was calculated by the following equation:
100-[(δF _inh / δF _con ) × 100]
Where δF is the change in fluorescence over the linear range of the curve. A non-linear curve fit was applied to the inhibition-concentration data and a 50% effective concentration (IC ₅₀ ) was calculated using Excel Xl-fit software.

All test compounds were found to have an IC ₅₀ of 9 μM or less. Preferred compounds had an IC ₅₀ of 0.021 μM and less than compound 58. Furthermore, while the compounds of the present invention uniformly showed greater potency against strain 1b compared to strain 1a, the test compound exhibited similar inhibitory properties against one or more types of NS3 / 4A complex. It turned out to show.

Specificity Tests Specificity tests were performed to show the selectivity of the compounds of the present invention in inhibiting HCV NS3 / 4A protease compared to other serine or cysteine proteases.

  The specificity of the compounds of the invention for various serine proteases was determined: human leukocyte elastase, porcine pancreatic elastase, and calf pancreatic α-chymotrypsin, one cysteine protease: human liver cathepsin B. In all cases, a 96-well plate format protocol using a colorimetric p-nitroaniline (pNA) substrate specific for each enzyme was used as described above (Patent WO 00/09543) with some modifications. .

  Each test was converted after ˜1% enzyme-inhibitor preincubation at rt, followed by substrate addition and hydrolysis to ˜30% as measured with a Spectramax Pro microplate reader. Compound concentrations varied from 100 to 0.4 μM depending on potency.

The final conditions and protocols for each test were the same as described above (Patent WO 00/09543), including other tests:
Contains 50 mM Tris-HCl pH8, 0.5 M Na ₂ SO ₄ , 50 mM NaCl, Ol mM EDTA, 3% DMSO, 0.01% Tween-20, and 1330 M succ-AAA-pNA and 20 nM elastase

The% inhibition is the formula:
[1-((UV _{inh −UV blank} ) / (UV _{ct1 −UV blank} ))] × 100
It calculated using.

A non-linear curve fit was applied to the inhibition-concentration data and a 50% effective concentration (IC ₅₀ ) was calculated using Excel Xl-fit software.

Tests based on HCV replicon cells HCV replicon whole cell lines were established as described in Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R., Science 285 (5424): 1103 (1999). . By this system, the effect of the HCV protease compound of the present invention on HCV RNA replication can be evaluated. In summary, using the HCV strain 1B sequence described in the Lohmann article (Accession No .: AJ238799), a 5 ′ intra-sequence ribosome entry site (IRES), a new gene, EMCV-IRES and HCV nonstructural proteins, NS3-NS5B and HCV cDNA encoding 3'NTR was produced. In vitro transcripts of cDNA were transfected into Huh7 cells and selection of cells that constitutively express the HCV replicon was performed in the presence of the selectable marker neomycin (G418). The resulting cell lines were examined for positive and negative RNA production and protein production over time.

Huh7 cells constitutively expressing the HCV replicon were grown in DMEM containing 10% FCS (fetal bovine serum) and 1 mg / ml G418 (Gibco-BRL). Cells were seeded the night before in 96-well tissue-culture sterilized plates (1.5 × 10 4 cells / well). Compounds in DMEM containing 4% FCS, 1: 100 penicillin / streptomycin, 1: 100 L-glutamine and 0.5% DMSO were prepared. Compound / DMSO mixture was added to the cells and incubated for 4 days at 37 ° C. After 4 days, cells are thawed using the Rneasy kit (Qiagen) and RNA isolated and purified for EC ₅₀ measurements or cells using Alamar Blue (Trek Diagnotstic Systems) for CC ₅₀ recording. Either toxicity was assessed. Purified total RNA for EC ₅₀ measurement was normalized using RiboGreen (Jones LJ, Yue ST, Cheung CY, Singer VL, Anal. Chem., 265 (2): 368-74 (1998)) and HCV RNA The relative amount of expression was measured using Taqmann's method (Kolykhalov AA, Mihalik K, Feinstone SM, Rice CM, Journal of Virology 74, 2046-2051 (2000)). In summary, RNA prepared in a volume of 5 μ1 (<1 ng) was prepared as follows: 5 × EZ rTth buffer, 3 mM MnOAc ₂ , 3 mM dNTPs, 200 nM forward primer, 600 nM reverse primer, lOOnM probe and rTth polymerase. -Added to Mix 20 μl. Samples containing known concentrations of HCV RNA transcripts were run as standards. Using the following cycling protocol (95 ° C, 1 min; 60 ° C, 0.5 min; 95 ° C, 2 min; 94 ° C, 0.5 min 40 cycles; 60 ° C, 1 min; and 60 ° C, 10 min completed) HCV RNA expression was quantified as described in the Perkin Elmer procedure. Toxicity of the compound (CC ₅₀ ) was measured by adding 1/10 volume of Alamar Blue to the medium in which the cells were incubated. After 4 hours, the fluorescence of each well was read at an excitation wavelength of 530 nM and an emission wavelength of 580 nM using a Cytofluor Series 4000 (Perspective Biosystems).

In vivo PK studies in rats All animal experiments were performed according to USDA guidelines under animal protection law. To assess systemic and hepatic exposure, representative compounds were administered to male Sprague-Dawley rats in which the jugular vein was placed, either orally (gastric intubation) or intravenously (bolus or infusion). Blood samples were collected continuously from the buried tube at a predetermined time after administration. Plasma was separated from EDTA-treated blood by centrifugation and stored at −20 ° C. until analysis. The liver was removed from the rat after death from suffocation with carbon dioxide, washed with saline, and dried with blotting paper. For analysis, the outer 2 g portion of one leaf was minced and homogenized with 4 ml of 80% acetonitrile / HBSS buffer. After centrifugation, the supernatant was maintained at −20 ° C. until analysis. Quantification of representative compounds in plasma and liver homogenate samples was performed by specific LC / MS / MS methods optimal for each compound.

Biological Samples Table 1 below lists representative compounds I of the present invention that were tested in vitro according to the methods described above.

Cell activity and specificity:
Representative compounds of the invention were evaluated in the HCV replicon cell test and some of the specificity tests outlined. For example, Compound 58 was found to have an IC ₅₀ of 17 nM against the NS3 / 4ABMS strain in an enzyme test. Similar titers were obtained with the published H77c (IC ₅₀ of LOnM) and J4L6S (IC ₅₀ of 8 nM) strains. In the replicon test, the EC ₅₀ value was 250 nM. This compound also showed ability for in vivo effects when the compound was administered orally or intravenously and subjected to viral target exposure.

  In the specificity test, the same compound was found to show the following activity: HLE = 35 μM; PPE> 100 μM; chymotrypsin> 100 μM; cathepsin B> 100 μM. These results indicate that this type of compound is remarkably specific to NS3 protease, and many of these inhibit HCV replicon replication.

The test compound was found to have the following range of activities:
IC ₅₀ activity range: A <50 μM; B <5 μM;
C is <0.5 μM; D is <0.05 μM
EC ₅₀ activity range: A <50 μM; B <5 μM;
C is <0.5 μM; D is <0.05 μM

Claims (18)

formula:

[Where
(a) R ₁ is Ri Oh optionally 1-3 times optionally substituted C _1-8 alkyl with halo or C _3-7 cycloalkyl le;
(b) m is 2 ;
(c) n is 1 or 2;
(d) R ₂ is C _1-6 alkyl or C _2-6 alkenyl Le, was or, R ₂ is H;
(e) R ₃ is, H, or optionally which may be C _1-8 alkyl substituted with phenyl, C _3-12 aralkyl key alkenyl, was or is a C _4-10 (alkylcycloalkyl), or , R ₃ together with the carbon atom to which it is attached form a C _3-7 cycloalkyl group substituted with C _2-6 alkenyl;
(f) Y is H, phenyl substituted with nitro, pyridyl substituted with nitro, or C _1-6 alkyl (wherein the alkyl may be optionally substituted with OH ) Is;
(g) B is, H, optionally by optionally C _1-6 alkyl substituted with _{OH, R 4 - (C =} O) -, R 4 O (C = O) -, C 1-10 alkyl - O— (C═O) — (C═O) —, or R ₄ SO ₂ — ; and
(h) R ₄ is
(i) optionally phenyl, carboxyl, 1 -3 halogen, hydroxy, -OC (O) C _1-6 alkyl, C _1-6 alkoxy sheet is a good C _1-10 alkyl optionally substituted with; or -O-phenyl optionally substituted with halogen or C _1-6 alkoxy;
(ii) optionally C _3-7 cycloalkyl luma other be substituted by hydroxy optionally is Ri C _4-10 alkylcycloalkyl der;
(iv) Tokoro by the Nozomu rehearsal androgenic, be phenyl optionally substituted with nitro;
(v) a furan ring;
(vi) Bicyclo (1.1.1) pentane;
(vii) -C (O) OC 1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl]
Or a pharmaceutically acceptable salt, solvate or prodrug thereof.   The compound of claim 1, wherein n is 1. The compound according to claim 1, wherein R ₁ is cyclopropyl. The compound of claim 1, wherein R ₂ is ethyl or vinyl. R ₃ is C _1-6 alkyl The compound of claim 1, wherein. _2. A compound according to claim 1 wherein n is 1 and R2 is ethyl. 7. A compound according to claim 6 , wherein R < ₁ > is cyclopropyl. The compound of claim 1, wherein n is 1 and R ₂ is vinyl. 9. A compound according to claim 8 , wherein R < ₁ > is cyclopropyl. formula:

[Where
(a) R ₁₁ is, C _1-8 alkyl, C _3-7 cycloalkyl or C _4-10 (Arukirushiku lower alkyl), naphthyl or phenyl (wherein, the phenyl is optionally halo, haloalkyl, Haloalkyloxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, —COOCH ₃ or optionally substituted 1-3 times with phenyl;
(b) R ₃ is C _1-8 alkyl or C _3-7 cycloalkyl ;
(c) Y is H ;
(d) B _{is, H, R 4 O (C} = O) - or _{R 4 -N (R 5) -C} (= O) - and is,
(e) R ₄ is
(i) C _1-10 alkyl optionally substituted with halo ; and
(ii) C _4-10 Arukirushiku lower alkyl der Ri;
(v) a tetrahydrofuran ring ; and
(f) R ₅ is C _1-6 alkyl substituted with H or halo ]
Or a pharmaceutically acceptable salt, solvate or prodrug thereof. _11. A compound according to claim 10 , wherein R11 is selected from cyclopropyl, cyclobutyl or optionally substituted phenyl. formula:

[Where
(a) R ₁₁ is located at C _1-8 alkyl or C _3-7 cycloalkyl le;
(b) R ₃ is, C _1-8 alkyl, or is optionally either a C _{2 -6} but it may also be substituted with alkenyl C _4-10 (alkylcycloalkyl), or, _{R 3} is , Together with the carbon atom to which it is attached , forms a C _3-7 cycloalkyl group substituted with C _2-6 alkenyl ;
(c) Y is H ;
(d) B _{is, H, R 4- (C =} O) -, R 4 O (C = O) -, or _{R 4 -N (R 5) -C} (= O) - and is,
(e) R ₄ is
(i) C _1-10 alkyl optionally substituted with halo ;
(ii) Ri C _3-7 cycloalkyl, C _3-7 cycloalkoxy, or C _4-10 Arukirushiku lower alkyl der; and
(f) R ₅ is H ]
Or a pharmaceutically acceptable salt, solvate or prodrug thereof. R ₁₁ is cyclopropyl, selected from cyclobutyl or phenyl which is optionally substituted, wherein compound of claim 12. formula:

[Where
(a) R ₁₁ is located in C _3-7 cycloalkyl le;
(b) R ₃ is located at C _1-8 alkyl le;
(c) Y is H ;
(d) B is R ₄ O (C═O) — ;
(e) R ₄ is
(i) is C _1-10 alkyl;
(g) n is 1 or 2;
(h) p is 1, 2 or 3 ]
Or a pharmaceutically acceptable salt, solvate or prodrug thereof. R ₁₁ is, according to claim 14 A compound according cyclopropyl. B is (CH ₃ ) ₃ C 2 O—CO—;
Y is H;
n is 1;
R ₁ is methyl, cyclopropyl or —CF ₃ ;
R ₂ is ethyl or vinyl; and
R ₃ is, t- butyl, i- propyl, s- butyl, i- butyl or cyclohexylmethyl compound according to claim 1, wherein. A pharmaceutical composition for the inhibition of HCV NS3 protease comprising:
(a) a compound according to any one of claims 1 16 or a pharmaceutically acceptable salt, solvate or prodrug thereof; and
(b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment of HCV infection,
(a) a compound according to any one of claims 1 16 or a pharmaceutically acceptable salt, solvate or prodrug thereof; and
(b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier.